Tissue-adaptive bioelectronic fibers with temperature-induced self-tightening enable ultrastable neural interface

Domain: neuroscience
Published: 2026-04-09
Editorial outcome: major_revision

Abstract
Neural interfaces are essential for brain-machine communication and closed-loop
neuromodulation. However, achieving durable interfaces between neural tissue and bioelectronics
remains a key challenge, as conventional electronics do not actively conform to the soft, tortuous
3D architecture of neural tissue. We report a tissue-adaptive bioelectronic fiber that actively
contracts to wrap around neural tissues, forming ultrastable neural-electronic interfaces, and
enabling highly reliable neural stimulation and recording. This fiber is fabricated via wet spinning
from a precursor integrating a thermoresponsive polymer and electroactive materials, and exhibits
an ultralow modulus of 0.16 MPa and a phase transition temperature of 26.7 °C. Upon contact with
rat tissue, the polymer chains undergo a hydrophilic-to-hydrophobic transition, expelling water
and contracting the fiber to conform tightly to the sciatic nerve. This ultrastable biointerface
demonstrates reliable neural stimulation, producing stable hindlimb bending responses, while
sciatic nerve action potential recordings show 99.5% signal retention under successive
stimulations.

Introduction
Bioelectronic-tissue interfaces are essential for neuroscience research, clinical therapies, and
neuromodulation1-11. As a crucial branch of neuromodulation, peripheral nerve modulation has
shown significant potential for regulating physiological functions and treating various diseases12,13.
For instance, vagus nerve stimulation has been applied to regulate heart rate, modulate
inflammatory responses, and manage drug-resistant epilepsy14,15. Similarly, stimulation of the
ulnar and sciatic nerves has proven effective in relieving chronic pain and restoring muscle
function16-18. Despite these promising applications, the clinical efficacy of peripheral nerve
modulation critically depends on the quality of the electrode-tissue interface, since instability at
the interface can degrade signal quality, reduce stimulation efficiency, and elevate stimulation
thresholds, ultimately limiting the reliability and therapeutic effectiveness of neuromodulation19-
21. Most therapeutic electrodes are fabricated from rigid materials such as platinum and silicon22,23.
These devices typically require partial penetration into neural tissue, increasing the risk of
inflammation and mechanical damage and thereby posing challenges for long-term therapeutic
efficacy24,25. In contrast, flexible film electrodes based on polymer substrates such as
polydimethylsiloxane (PDMS) or parylene-C, combined with electroactive materials including
gold nanoparticles or polypyrrole (PPy), have emerged as promising alternatives26,27. Owing to
their soft and flexible structure, these electrodes can conform closely to neural tissue, thereby
minimizing implantation-induced damage while maintaining high electrical conductivity.
However, under dynamic physiological conditions, such film electrodes often lose intimate contact
with surrounding tissue, resulting in interfacial gaps and subsequent signal degradation or even
therapeutic failure in clinical applications. To address this limitation, enhancing adhesion at the
electrode-tissue interface has become an effective strategy for ensuring stable and continuous
bioelectronic integration under wet and/or dynamic environments.

Current approaches to improve electrode-tissue interface stability mainly rely on interfacial
adhesion mechanisms that involve physical interactions and covalent bonding28,29. Physical
interactions, including hydrogen bonding, van der Waals forces, electrostatic attraction, and
mechanical interlocking, provide reversible adhesion but only moderate adhesion strength30,31.
Covalent bonding, typically introduced through reactive groups such as amino (–NH ), carboxyl
2
(–COOH), and thiol (–SH) on electrode surfaces, forms irreversible chemical linkages with
tissues32,33. This markedly enhances electrode-tissue interfacial stability, even under dynamic
conditions. However, the irreversible nature of such bonding can hinder device removal and
increase the risk of tissue damage.

To address these limitations, active conformal strategies based on smart actuation have been
developed. Smart polymers play a crucial role in these approaches, as their stimulus-responsive
deformation enables active conformity to soft tissue. For example, shape-memory polymer thin-
film electrodes achieve conformal tissue contact through thermally triggered shape recovery of a
deformable polymer substrate carrying metal nanofilm electrodes34. Electrochemically actuated
PPy-based electrodes regulate electrode-tissue contact through voltage-induced redox reactions
that cause reversible expansion and contraction27. Similarly, water-responsive polymer electrodes
based on oriented semicrystalline poly(ethylene oxide) undergo rapid contraction upon exposure
to tissue fluids, enabling tight tissue wrapping through hydration-induced recoiling of amorphous
polymer chains35. Despite these advances, most existing designs still rely on externally applied
stimuli to achieve conformal adaptation. Moreover, film-type electronic devices often struggle to
interface effectively with the intricate, small-scale structures of neural tissues due to geometric
mismatch. Therefore, it is critical to develop advanced bioelectronic devices that can actively adapt
to the complex geometry of small neural tissues through endogenous stimuli, enabling more stable
and efficient signal transmission.

Here, we report a tissue-adaptive bioelectronic fiber that undergoes thermo-triggered contraction
driven by endogenous tissue temperature, allowing the formation of stable biointerfaces. When
interfaced with living tissue, the fiber responds to intrinsic temperature by undergoing a phase
transition, resulting in autonomous contraction and self-tightening without external actuation. The
bioelectronic fiber is designed as a composite hydrogel system integrating a thermoresponsive
poly(N-isopropylacrylamide) (PNIPAm) matrix, polypyrrole-modified carboxylated multi-walled
carbon nanotubes (PPy@CNT), and biocompatible sodium alginate (SA), fabricated via a scalable
wet-spinning process. The resulting PNIPAm/SA/PPy@CNT (PSPC) fibers possess mixed ionic-
electronic conductivity while maintaining mechanical compliance with soft tissues. Owing to its
one-dimensional microscale geometry and thermo-adaptive behavior, the bioelectronic fiber
enables stable and adaptive interfacing with soft and curved tissues. We further demonstrate its
potential for reliable neural interfacing in vivo, highlighting bioelectronic fibers as a promising
platform for constructing stable electrode-tissue interfaces.

Results
Fabrication and characterization of tissue-adaptive bioelectronic fibers
The tissue-adaptive bioelectronic fibers exhibit pronounced thermo-adaptive contraction, leading
to autonomous tightening around surrounding tissues. This contraction behavior is functionally
analogous to the active tightening of a snake coiling around its prey, resulting in stable interface
(Figs. 1a, b). To evaluate this self-tightening and conformal behavior across tissues with different
geometries and curvatures, the sciatic nerve, kidney, skeletal muscle, and heart of rats were
selected. In all cases, the tissue-adaptive bioelectronic fibers formed stable conformal contact with
these tissue surfaces (Fig. 1c).

To fabricate bioelectronic fibers, the spinning solution consisting of PNIPAm, SA, and
polypyrrole-modified carboxylated multi-walled carbon nanotubes (PPy@CNT), was extruded
into an aqueous Ca2+-based coagulation bath (Fig. 2a)36,37. The synthesis and characterization of
the individual components are detailed as follows. PNIPAm was selected as the temperature-
sensitive polymer owing to its good biocompatibility and a phase transition temperature of ~ 32 °C
close to physiological temperature38,39. PNIPAm was synthesized via free-radical polymerization
of NIPAm in aqueous solution and subsequently purified by dialysis, yielding a polymer with a
molecular weight of ~ 4.9×105 g/mol and a dispersity of 2.3 (Supplementary Fig. 1). PPy@CNT
was obtained through Fe3+-catalyzed in situ polymerization of pyrrole on carboxylated carbon
nanotubes. Scanning electron microscopy (SEM) images revealed a coating layer on the CNT
surface, suggesting successful PPy deposition (Supplementary Fig. 2). By tuning the concentration
of pyrrole monomers, PPy@CNT composites with different PPy loadings were obtained. The
samples were denoted as PPy @CNT , where x and y represent the mass ratio of PPy to CNT,
x y
respectively. Details are provided in the Methods section. The Fourier-transform infrared (FTIR)
spectra showed that the C-O stretching band of -COOH groups in CNT at 1168 cm−1 became
indistinct in PPy@CNT. Meanwhile, the characteristic absorption peaks of PPy (1459, 1307, and
1045 cm−1) exhibited a blue shift compared with those of pure PPy and CNT, indicating interfacial
interactions between CNT and PPy (Supplementary Fig. 3). The obtained PNIPAm/SA/PPy@CNT
(PSPC) fiber exhibited reversible volume changes, with pronounced shrinkage observed above its
volume phase transition temperature (VPTT) (Fig. 2b). The fiber contracted at elevated
temperatures and recovered upon cooling, due to the thermally induced collapse of the polymer
network.

The morphology and mechanical properties of the PSPC fiber were further characterized. The dried
fiber showed a diameter of approximately ~345 μm. SEM images revealed a smooth surface and
a crack-free cross-section (Figs. 2c-f). The elongation at break and Young's modulus of the PSPC
fiber were 168% and 160 kPa, respectively, compared with 91% and 60 kPa for PNIPAm/SA (PS)
fibers (Supplementary Fig. 4). This increase in mechanical properties is associated with hydrogen
bond interactions between PPy@CNT and the polymer matrix40,41. To verify these interactions,
FTIR analysis was performed. Compared with PS, the -OH stretching band in PSPC shifted from
3438 to 3424 cm−1, and the C=O stretching band shifted from 1650 to 1629 cm−1, suggesting
enhanced hydrogen-bonding interactions between PPy@CNT and the PNIPAm-SA composite
(Supplementary Fig. 5). The Young's modulus of the PSPC fiber was ~160 kPa, smaller than that
of rat sciatic nerve tissue ~580 kPa42, which may facilitate better mechanical compliance and
highlight its potential for neural applications. To evaluate the structural integrity of PSPC fibers
under physiologically relevant conditions, immersion tests were conducted in PBS at 37 °C for up
to 12 h. Only minor changes in mass and diameter were observed over time, indicating stable fiber
structure (Supplementary Fig. 6).

Thermoresponsive properties and finite element analysis
The thermoresponsive behavior of PSPC fibers was first evaluated to examine their potential for
temperature-induced self-adaptive conformability to neural tissues. Differential scanning
calorimetry (DSC) was performed from 10 to 50 °C at a heating rate of 5 °C/min. The endothermic
peak observed in the DSC curve corresponds to the phase transition of the polymer network.
PNIPAm aqueous solutions are widely reported to exhibit a phase transition at ~32 °C43. In contrast,
as shown in Fig. 3a, the phase transition temperature of PS fibers decreased to 23.5 °C, consistent
with the salt-induced reduction in transition temperature44,45. This shift is likely caused by
interactions between Ca2+ and the amide oxygen atoms of PNIPAm, which weaken PNIPAm-water
hydrogen bonding and promotes hydrophobic aggregation and chain contraction at lower
temperatures. Incorporation of PPy@CNT partially offset this decrease, raising the transition
temperature to 26.7 °C in PSPC fibers. This increase can be attributed to hydrogen-bonding
interactions between hydrophilic functional groups on PPy@CNT and the PNIPAm/SA matrix,
which enhance water retention within the polymer network. The increased hydration suppresses
PNIPAm chain aggregation, resulting in an upward shift in temperature. Importantly, the transition
temperature of PSPC fibers remained well below physiological temperature, indicating their
suitability for implantable bioelectronic applications. As mentioned above, the PSPC fibers
experience water expulsion and shrinkage when exposed to heat. Therefore, the water loss ratio
and fiber diameter were measured as indicators of its thermo-responsive deformation. Owing to
its low transition temperature of 26.7 °C, the fibers responded quickly when placed in phosphate-
buffered saline (PBS) at 37 °C. Within 30–50 s, the water loss ratio increased from 10% to 20%,
while the diameter decreased from 410 μm to 360 μm (Fig. 3b). This rapid dehydration and
shrinkage indicate the high sensitivity of fiber to physiological temperature. Moreover, the PSPC
fibers showed reversible size changes during repeated heating and cooling. Its diameter decreased
from 450 μm at 25 °C to 350 μm in PBS at 37 °C, and returned to 450 μm upon cooling back to
25 °C (Fig. 3c). These reversible volume changes confirm the thermo-responsive behavior of the
PSPC fibers and demonstrate their stability and reusability under cyclic conditions.

In vitro simulation tests were carried out to evaluate the tissue-adaptive behavior of PSPC fibers.
To mimic the morphology and mechanical properties of sciatic nerve fibers, soft PDMS was used
to prepare fiber-like structures similar to native nerves, with a modulus of ~380 kPa and a diameter
of ~1.3 mm (Supplementary Fig. 7). PSPC and SA/PPy@CNT (SPC) fibers were first wrapped
around PDMS fibers. Due to their softness, both types of fibers could be physically wound onto
the PDMS. The samples were then immersed in PBS at 37 °C to mimic the physiological
conditions. Upon immersion, the SPC fibers began to detach from the PDMS because of weak
physical interactions. In contrast, the PSPC fibers underwent thermally induced contraction,
forming a tighter interface with the PDMS. When the PDMS fibers were shaken in PBS, PSPC
fibers remained firmly attached, whereas nearly half of the SPC fibers detached. Furthermore,
when one end of the fibers was lifted from the solution, the PSPC fibers pulled the PDMS fiber up
together, while the SPC fibers immediately detached (Fig. 3d, Supplementary Movies 1, 2). These
results indicate that the PSPC fibers can self-adaptively tighten around PDMS fibers, forming a
stable and robust interface. To further evaluate their dynamic thermoresponsive behavior, a PSPC
fiber was wrapped around a PDMS fiber and placed in a temperature-controlled chamber at 37 °C.
The fiber completed self-adaptive contraction within 3 s (Supplementary Movie 3). Finite element
analysis showed that the normal stress generated by PSPC fibers during deformation was only ~3
kPa (Fig. 3e), which is below commonly reported thresholds associated with acute nerve
compression injury of ~9 MPa46. In addition, blood flow after PSPC implantation was
systematically evaluated. No statistically significant (P = 0.08) differences were observed
compared with the sham-operated control group, as indicated by the relative blood flow index
derived from laser speckle contrast imaging (Supplementary Fig. 8). These results suggest that
PSPC implantation does not significantly affect local blood flow.

Electrochemical characterization
The electrochemical property of bioelectronic fibers in PBS were tested to assess their reliability
in neural electrical stimulation and recording. Electrochemical impedance spectroscopy (EIS) was
carried out under sinusoidal conditions with an amplitude of 5 mV and frequency range of 1 Hz to
100 kHz. The impedance characteristics of PS, PNIPAm/SA/PPy (PSP), and PSPC fibers were
comparatively evaluated. At 1 kHz, PS fibers exhibited a high impedance of 8064 Ω, which
decreased to 4370 Ω after the incorporation of PPy in PSP fibers. A further reduction was observed
for PSPC fibers containing PPy@CNT (Fig. 4a, and Supplementary Fig. 9). Specifically, as the
PPy-to-CNT mass ratio in PSPC fibers increased from 0.3 to 1.2, the impedance gradually
decreased to ~2.0 kΩ at 1 kHz (Supplementary Fig. 10). These results show that CNT incorporation
effectively reduces the impedance of fibers. The stretchability of PSPC fibers initially increased
with increasing PPy-to-CNT mass ratio, followed by a decline at higher ratios (Supplementary Fig.
11). Considering both impedance and mechanical properties, a PPy-to-CNT mass ratio of 0.8 was
identified as the optimal ratio. Unless otherwise specified, PSPC fibers in the following sections
refer to this composition. In addition, PSPC fibers exhibited lower phase angles at low frequencies
compared with PS fibers, indicating a reduced phase delay between current and voltage. This
reduction in phase lag improves the temporal responsiveness of the current, thereby facilitating
rapid charge delivery during neuroelectric stimulation (Fig. 4b). Other nanomaterials, including
silver nanowires (AgNW) and polyaniline (PANI) nanorods, were also used as conductive fillers
to fabricate similar fibers. These fibers exhibited comparable initial impedance. However, the
impedance of the PANI- and AgNW-based fibers increased during immersion in PBS, whereas the
CNT-based fibers remained stable (Supplementary Fig. 12), owing to the higher chemical and
physicochemical stability of CNT.

A higher charge injection capacity (CIC) enables more efficient charge transfer at the electrode-
tissue interface, thereby allowing more effective electrical stimulation. The CIC of PSPC fibers
increased markedly to 10 μC cm⁻2, about 35 times higher than that of PS fibers, which had a CIC
of 0.28 μC cm⁻2 (Fig. 4c, Supplementary Fig. 13). In addition, the charge storage capacity (CSC)
of PSPC fibers was 0.84 mC cm⁻2, nearly nine times higher than that of PS fibers, which was
0.093 mC cm⁻2 (Fig. 4d). It also exceeds the 0.65 mC cm-2 observed for PSP fibers, indicating the
important role of CNT in improving the electrochemical performance (Supplementary Fig. 14).
This enhanced CSC can promote signal transmission, ensuring efficient stimulation and reliable
recording. The improved performance results from the synergistic combination of the highly
conductive CNT and the electrochemically active PPy. Notably, the electrochemical performance
under physiological conditions is a critical factor for neural interfacing. The charge storage and
transport characteristics of PSPC fibers remained stable at 37 °C, showing negligible change,
which indicates good suitability for in vivo applications (Supplementary Figs. 15-17).

Electrochemical stability of PSPC fibers at physiological temperature was evaluated by cyclic
voltammetry (CV). Notably, the CV curves obtained during cycling were highly overlapping, and
a 97% CSC retention was observed after 100 cycles, indicating the excellent electrochemical
stability of PSPC fibers (Figs. 4e, f). Moreover, CV curves showed a gradual increase in the
enclosed area as the scan rate increased from 20 to 500 mV s⁻1, indicating an enhanced current
response. This behavior suggests a hybrid capacitive mechanism governed by both surface redox
reactions and ion diffusion processes (Fig. 4g). Galvanostatic charge-discharge (GCD)
measurements were performed at various current densities within the potential window of –0.5 to
0.5 V to evaluate the charge-discharge behavior of the fibers. All GCD curves showed nearly
symmetrical triangular shapes across different current densities, indicating well-matched charge
and discharge processes and good electrochemical reversibility of the bioelectronic fibers (Fig. 4h).
Furthermore, the electrochemical stability of the bioelectronic fibers was evaluated by soaking
them in PBS at 37 °C for different durations. They exhibited good stability, with only a slight
impedance change observed after 1 h of soaking (Fig. 4i).

Cytocompatibility and in vivo biocompatibility
The cytocompatibility of the bioelectronic fiber was systematically evaluated. PSPC fibers were
cultured with mouse fibroblasts (L929) to assess cell viability, and cytotoxicity was examined
using CCK-8 assays. Live/dead staining showed that the density of viable L929 cells increased
progressively during the culture period, comparable to that of the control group (Fig. 5a).
Consistently, the optical density (OD) values at 450 nm of cell cultures with PSPC fibers also
increased over time, showing no significant difference from the control group (Fig. 5b). In addition,
the survival rates of cells in the PSPC group remained above 90% (Supplementary Fig. 18),
confirming the non-toxicity of PSPC fibers. Likewise, SPC fibers also exhibited good
cytocompatibility after co-culture with L929 cells (Supplementary Figs. 19-21). To assess in vivo
biocompatibility, PSPC fibers were implanted subcutaneously in the dorsal region of rats for one
week. Hematoxylin and eosin (H&E) staining showed no apparent inflammatory response around
the implanted fibers compared with the sham controls. Immunofluorescence staining for α-smooth
muscle actin (α-SMA) and cluster of differentiation 68 (CD68) further revealed no significant (P
= 0.82 for α-SMA; P = 0.75 for CD68) inflammatory or foreign body responses around the
implanted fibers, indicating good in vivo biocompatibility (Figs. 5c-e).

In vivo electrical stimulation and electrophysiological recording
Electrical stimulation of the sciatic nerve was performed to evaluate the in vivo stimulation
performance of the bioelectronic fibers. During stimulation, hindlimb muscle contractions
produced mechanical motion that could destabilize the electrode-nerve interface. PSPC fibers were
wound around the sciatic nerve of rats and closely conformed to its highly curved surface owing
to their thermally induced contraction. This self-adaptive behavior formed a stable and intimate
fiber-nerve interface under dynamic conditions. Under electrical stimulation, clear hindlimb
bending was observed (Figs. 6a, b), indicating effective neural activation and motor responses.

To further evaluate the role of the electrode-nerve interface in stimulation effect, SPC fibers, which
lack the self-contraction function but exhibit comparable electrochemical characteristics, were
used as controls (Supplementary Figs. 13, 22-24). SPC and PSPC fibers were wrapped around the
sciatic nerve and subjected to the same stimulation conditions. As shown in Fig. 6c, both types of
fibers exhibited similar stimulation effects, including movement angle and tension force, at the
beginning of stimulation. After multiple stimulations, however, the response induced by SPC fibers
declined markedly, with the movement angle and tension force dropping to 25.5% and 35.2% of
their initial values, respectively. In contrast, PSPC fibers induced stable responses with minimal
variation (Figs. 6d, e). Notably, stable responses were also maintained over a longer period of three
hours and across different stimulation frequencies, with stimulations delivered at one-hour
intervals (Supplementary Fig. 25). Furthermore, the movement angle increased progressively with
higher stimulation currents (Supplementary Fig. 26), indicating effective and controllable
stimulation. These results demonstrate that the self-adaptive PSPC fibers form a stable fiber-nerve
interface that enables effective electrical stimulation.

The bioelectronic fibers were employed to synchronously record compound nerve action potentials
(CNAP) evoked by neural stimulation. The recording system consisted of a recording electrode, a
reference electrode, and a ground electrode, all of which self-adaptively conformed to the sciatic
nerve to form an ultrastable and intimate interface, thereby enabling reliable signal acquisition
(Fig. 6f). The CNAP of sciatic nerve were synchronously recorded in response to pulsed current
stimulation at different amplitudes. With increasing stimulation amplitude, the CNAP signals were
progressively enhanced, indicating that the stable and conformal fiber-nerve interface enables
accurate and reliable neural recording (Fig. 6g). The cycling stability of neural recordings was also
evaluated. As shown in Fig. 6h, the CNAP signals recorded by PSPC fibers remained stable over
1000 consecutive stimulations, retaining 99.5% of the signal intensity (Supplementary Fig. 27).
The corresponding power spectral density remained nearly unchanged, indicating stable interfacial
contact and signal acquisition. The stable interface formed by the self-adaptive bioelectronic fibers
supports reliable neural monitoring under tissue motion.

In addition to forming stable neural interfaces for signal recording, PSPC fibers can also be applied
at muscle interfaces to monitor other bioelectrical signals, such as compound muscle action
potentials (CMAP). To evaluate their recording performance, PSPC fibers were wound around the
extensor digitorum longus muscle (EDL) of rats. A stimulation current was delivered to the sciatic
nerve using commercial needle electrodes, and clear CMAP signals were simultaneously recorded
from the EDL using PSPC fibers (Supplementary Fig. 28a). The PSPC fibers maintained stable
signals with up to 99.8% intensity retention over a 3 h period, owing to the stable electrode-muscle
interface formed by self-contraction. For comparison, SPC fibers without the self-contraction
function were used as control bioelectrodes. Signals recorded with SPC fibers gradually decreased,
with only 34.2% intensity retention (Supplementary Figs. 28b, c).

Methods
Materials
Sodium alginate (SA, 200 ± 20 mpa·s), N,N,N',N'-tetramethylethylenediamine (TEMED), ferric
chloride (FeCl , 98%) and silver nanowires (AgNW, 45 μm length, 70 nm diameter), were
3
purchased from Shanghai Aladdin Biochemical Technology Co., Ltd. Polydimethylsiloxane
(PDMS, Sylgard 184) was obtained from Dow Corning Corporation. Anhydrous calcium chloride
(CaCl ), N-isopropylacrylamide (NIPAm), pyrrole (99%), chloral hydrate, N,N-
2
dimethylformamide (DMF) and sodium dodecyl benzene sulfonate (SDBS) were purchased from
Shanghai Titan Technological Co., Ltd. Potassium persulfate (KPS) was obtained from Sinopharm
Chemical Reagent Co., Ltd. Physiological saline (pH = 7.0, 0.9%) was supplied by Shanghai
yuanye Bio-Technology Co., Ltd. Carboxylated multi-walled carbon nanotubes (CNT, 10-20 μm
length, 30-50 nm diameter), and polyaniline (PANI) nanorods (0.5-2 μm length, 80-100 nm
diameter), were supplied by Jiangsu Xianfeng Nanomaterials Technology Co., Ltd. Phosphate-
buffered saline (PBS), penicillin-streptomycin, trypsin-EDTA, fetal bovine serum (FBS), and
Dulbecco modified Eagle medium (DMEM) were purchased from Gibco Life Technologies Co.
(USA). The cell counting kit-8 (CCK-8) and calcein-AM/propidium iodide (PI) double staining
kit were obtained from Dojindo Molecular Technologies, Inc. (Japan). The male Sprague-Dawley
(SD) rats (180–200 g) were supplied by Shanghai SLAC Laboratory Animal Co., Ltd. The yellow
dye for staining the PDMS fibers was purchased from Shenzhen Magic Color Technology Co., Ltd.
The mouse fibroblasts (L929) were obtained from the Stem Cells Bank (Chinese Academy of
Sciences, China). Stimulating electrodes made of stainless steel were purchased from Wuxi Jiajian
Medical Instrument Co., Ltd. Anti‑CD68 rabbit polyclonal antibody (1:500, 28058-1-AP) was
purchased from Proteintech Group, Inc. (USA). Anti-α-smooth muscle actin antibody (1:2000,
BM0002), Cy3 Conjugated AffiniPure Goat Anti-Rabbit IgG (H+L) (1:300, BA1032) and Cy3
Conjugated AffiniPure Goat Anti-Mouse IgG (H+L) (1:300, BA1031) were purchased from Boster
Biological Technology Co., Ltd. (China).

Preparation of PNIPAm solution
0.5 g of NIPAm was dissolved in 6.0 g of deionized water, followed by the addition of 0.02 g of
KPS (initiator) and 0.015 mL of TEMED (catalyst) and stirred thoroughly to obtain the mixed
solution. Ultrasonication was then performed in an ice bath (< 5 °C) for 30 min and then allowed
to react for 12 h for free radical polymerization (72% yield). A pure PNIPAm solution with a
polymer content of 6% was obtained by dialysis, which ensured the complete removal of residual
monomer.

Preparation of PPy@CNT
CNT (1.0 g) was added to 5 mL of 0.03 M SDBS solution, stirred for 1 h, followed by ultrasonic
dispersion for 3 h. Subsequently, 0.58 g, 1.45 g, and 2.03 g of pyrrole monomer was added to the
dispersion and stirred for 30 min under an ice bath. Polymerization was initiated by the slow
dropwise addition of 1 mL of 5 M FeCl solution using a dropping funnel, and the reaction was
3
maintained under ice-bath conditions for 12 h. After completion, the products were washed with
anhydrous ethanol until colorless and dried under vacuum at 50 °C for 24 h to obtain PPy@CNT
composites with different PPy-to-CNT mass ratios. The PPy content was determined by weighing
the CNT before and after the polymerization of pyrrole. The composite samples were denoted as
PPy @CNT , where x and y represent the mass ratio of PPy to CNT, respectively. PPy
x y
nanoparticles were synthesized by polymerization of pyrrole (140 μL) in 50 mL of 5 M FeCl
3
aqueous solution under an ice bath for 12 h, followed by centrifugation and washing with
anhydrous ethanol.

Preparation of fibers
All fibers were fabricated by injecting the corresponding spinning solutions into a 5 wt% CaCl
2
coagulation bath. The PNIPAm/SA (PS) spinning solution was prepared by mixing 5.0 g of
PNIPAm aqueous solution, 0.08 g of SA, and 1.0 g of deionized water. For the preparation of
PNIPAm/SA/PPy (PSP) fibers, the spinning solution was obtained by mixing 5.0 g of PNIPAm
aqueous solution, 0.08 g of SA, 10 mg of PPy, and 1.0 g of deionized water. A PPy@CNT
dispersion was first prepared by dispersing 10 mg of PPy@CNT in 1.0 g of deionized water. Then,
the resulting dispersion was mixed with 0.08 g of SA and 5.0 g of water to obtain the
SA/PPy@CNT (SPC) spinning solution. The PNIPAm/SA/PPy@CNT (PSPC) spinning solution
was prepared by mixing 5.0 g of PNIPAm aqueous solution, 0.08 g of SA, and 1.01 g of the
PPy@CNT dispersion. Three spinning solutions (PNIPAm/SA/CNT, PNIPAm/SA/AgNW, and
PNIPAm/SA/PANI) were prepared by mixing of 5.0 g of PNIPAm aqueous solution, 0.08 g of SA,
1.0 g of water, and 10 mg of the corresponding conductive material. Each spinning solution was
injected into the coagulation bath using a syringe with a 0.26 mm needle at an injection rate of 0.2
mL/min. Fibers formed rapidly when the spinning solution was injected into the coagulation bath.
After ~ 20 min of gelation, the fibers were collected and rinsed three times with deionized water.

Preparation of stained PDMS fiber
Stained PDMS fibers with a diameter of 1.3 mm were fabricated using a polymer mold by curing
a PDMS prepolymer/curing agent mixture containing yellow dye. The mixture, prepared at a 20:1
mass ratio of base to curing agent, was cured at 100 °C for 3 h, followed by demolding.

Electrochemical property measurement
The electrochemical workstation (CHI660E, Shanghai Chenhua Instrument Co., Ltd., China) was
used to perform electrochemical impedance spectroscopy (ElS), cyclic voltammetry (CV), charge
injection capacity (CIC) and galvanostatic charge-discharge (GCD) measurements in a 0.1 M PBS
solution with a standard three-electrode configuration. A 1 cm bioelectronic fiber with a diameter
of approximately 450 μm, containing 2.8 wt% PPy@CNT in the polymer matrix, was immersed
in PBS and placed between sandwiched between two platinum (Pt) electrodes as the working
electrode. An Ag/AgCl served as the reference electrode, and a Pt sheet (1 cm × 1 cm) was used
as the counter electrode. For EIS measurements, a 5 mV amplitude was applied with a frequency
sweep from 100 to 105 Hz. CV tests were conducted in the range of −0.5~0.5 V at scanning speed
of 20–500 mV/s. CIC was measured by applying biphasic pulses of ±0.5 V with a duration of 0.5
ms versus the Ag/AgCl reference electrode. GCD measurements were conducted between −0.5
and 0.5 V (vs Ag/AgCl) at current densities from 0.1 to 1 mA cm–2.

Finite element analysis
The simulation explaining the contractile self-fixing behavior of PSPC fibers was analyzed using
3D modeling in COMSOL Multiphysics (version 6.0) software. The normal stresses on the neural
model were simulated for the fiber model at 25 °C and 37 °C. The thermal expansion coefficient
(𝛼) of the PSPC fiber is approximately –2 × 10–4 1/k. The thermal expansion coefficient (𝛼) was
calculated by Eq. (1):
∆𝐿
L𝛼 = 
𝐿 ∙∆𝑇
0
where L is the initial length of the fiber, ∆L denotes the change in fiber length induced by
0
temperature variation, and ∆T represents the change in temperature.

Water loss ratio measurement
Water loss ratio (WLR) was calculated by Eq. (2):
𝑚 −𝑚
t d
𝑊𝐿𝑅 = (1− )×100%
𝑚 −𝑚
0 d
where m , m, and m represent the initial, thermal treatment, and dry weights, respectively.
0 t d

Characterization
The structure was observed using the cold field emission scanning electron microscope (SU-8010,
Hitachi). Fourier transform infrared spectroscopy (FT-IR) spectra were recorded using the Fourier
transform infrared spectrometer (Nicolet iS50, PerkinElmer). The mechanical properties of fibers
were tested by a universal tensile testing machine (UTM2103, Shenzhen Suns technology). The
tension generated during rat hindlimb movement was recorded with a biometric signal acquisition
and analysis system (RM6240E, Chengdu Instrument Factory) with a muscle tension transducer
(JZJ01, Chengdu Instrument Factory). The phase transition temperature of the fibers were obtained
by differential scanning calorimetry (DSC 3500, NETZSCH Instruments). The Molecular weight
of PNIPAm was determined by gel permeation chromatography (Agilent 1260 Infinity Ⅱ, Agilent
Technologies) with N,N-dimethylformamide as solvent at 25 °C.

Stability of PSPC fibers
PSPC fibers were immersed in PBS at 37 °C for differnt times. At each time point, fibers were
removed, blotted dry, and weighed. Fiber diameters were measured at 37 °C by optical microscopy
at multiple positions, and the mean values were calculated.

Blood flow detection
Blood flow was assessed using a 2LD laser speckle imaging system (OMEGAZONE OZ-2,
OMEGAWAVE, Inc.). The CCD camera captured speckle images of blood flow with an acquisition
time of 1 s at a defined blood vessel location on the nerve surface. The laser speckle intensity
scattered by flowing blood corpuscles was visualized as color-coded speckle maps, from which
the relative blood flow index (a.u.) was calculated over a 30 s measurement period. All
measurements were repeated for four independent samples, and the results are presented as mean
± standard deviation.

Cytocompatibility assessment
The L929 was used as the cell model to evaluate the effects of PSPC and SPC fibers on cell
behaviors. The PSPC and SPC fibers were cut into 2 cm segments, sterilized with 75% alcohol for
30 min, and then irradiated with UV light for 1 h. The fibers were washed with PBS before cell
seeding. L929 cells were cultured in DMEM with 10% FBS and 1% penicillin-streptomycin
solution. Then, cells were seeded on the sterilized fibers at the density of approximately 2×104
cells/well and cultured in the a 5% CO incubator at 37 °C. After culturing for 1, 3 and 5 days, the
2
cell viability and proliferation were assessed using the CCK-8 assay. Briefly, the CCK-8 reagent
was added to each well followed by incubation for 1 h. Then, the absorbance of the supernatants
was measured at 450 nm using the microplate reader (Multiskan FC, Thermo FisherScientific,
USA). At the same time, the fibers were stained using propidium iodide and calcein-AM (2 μM,
Beyotime Biotech, China) for 30 min at 37 °C. Lastly, the live/dead cells were observed with the
fluorescence microscope (Ti-s, Nikon, Japan).

Biocompatibility assessment
In vivo biocompatibility was evaluated by assessing the inflammatory and immune response of
dorsal subcutaneous tissue after implantation of PSPC fibers for one week, with a sham-operated
group serving as the control. Each group consisted of four male SD rats (6-8 weeks old). Rats were
anesthetized with 0.8 mL of 10 wt.% chloral hydrate, and a 1-2 cm dorsal incision was made to
create a subcutaneous pocket for implantation of PSPC fibers (~5 mm in length); sham animals
underwent identical procedures without implantation. Incisions were sutured and saline was
injected subcutaneously. After one week, peri-implant and sham tissues were collected, fixed,
paraffin-embedded, sectioned, and subjected to H&E staining. For immunofluorescence, sections
were antigen-retrieved using citrate buffer for α-SMA or EDTA buffer for CD68, incubated with
primary antibodies overnight at 4 °C, followed by Cy3-labeled secondary antibodies. Nuclei were
counterstained with DAPI, and images were acquired using a Nikon Eclipse fluorescence
microscope. Image quantification was performed using ImageJ (v1.53k), and statistical analysis
was conducted with Origin 2021.

Stimulation and recording experiment
For sciatic nerve stimulation, CNAP recording, and CMAP recording, four male SD rats (6-8
weeks) were used for each experiment. The SD rats were anesthetized by intraperitoneal injection
of chloral hydrate at a dose of 350 mg/kg body weight before surgery. The rats were then fixed on
a stereotaxic apparatus. The hair over the surgical area was shaved, and the skin was incised to
expose the sciatic nerve. PSPC fibers were gently positioned alongside the exposed sciatic nerve
and manually wound around the nerve with fine forceps, forming three to five closely spaced turns.
After self-shrinking to achieve conformal and stable contact with the nerve, cathode-first, charge-
balanced electrical pulses (150 μA, 1–5 Hz) were delivered through PSPC fibers using a
multichannel biosignal acquisition system (RM6240E, Chengdu Instrument Factory). For action
potentials recording, commercial needle electrodes were used for sciatic nerve stimulations (300
μA, 0.5–1 Hz). CNAP and CMAP recordings were performed in separate experiments. CNAP was
recorded from PSPC fibers integrated with the sciatic nerve as described above, whereas CMAP
was recorded from fibers integrated with the EDL using the same procedure. The signals were
acquired with an RM6240E system and analyzed in MATLAB 2024b.

Action potential signal retention analysis
The action potential signal retention ratio was calculated as the ratio of the signal amplitude after
repeated electrical stimulation to that after the initial stimulation. The signal amplitude was
determined as the difference between the maximum positive peak and the minimum negative
trough.

Statistical analysis
All measurements were performed on four independent samples, and data are presented as mean
± SD. Statistical analysis between two groups were conducted using a two-sided Student’s t-test.
Statistical significance was defined as p ≤ 0.05.

Animal experiment protocols
All animal experiments were approved by the Institutional Animal Care and Use Committee of
Donghua University (No. DHUEC-NSFC-2023-48).

Peer review rounds
[{"round": 1, "reviewer_comments": {"reviewer_1": "I have thoroughly evaluated the manuscript entitled “Tissue-adaptive bioelectronic fibers with temperature-induced self-tightening enable ultrastable neural interface” (Manuscript Number: NCOMMS-25-86621) submitted by Pan et al. Please find below my comments and suggestions for improvement. The manuscript may be considered for publication after the revision.\nComments:\n1. It is not evident whether the authors have evaluated the properties of the system in the absence of CNTs. If such a comparison has not been performed, the authors are strongly encouraged to investigate the properties of the fibers without CNTs to clearly demonstrate the contribution of CNT incorporation. Moreover, the authors should clarify whether alternative nanotube (instead of CNTs) can be used in this system or not.\n2. The authors should evaluate the stability of the fabricated fibers after immersion in PBS buffer over different time intervals. This will help understand their structural integrity and suitability for potential applications.\n3. Figure 3a and Figure 6 (SI) should be merged into a single plot to enable a clearer and more direct comparison. Additionally, the authors are encouraged to use an alternative method to validate the cloud-point temperature (TCP) and strengthen the reliability of the reported results.\n4. In general, hydrophilic sodium/calcium alginate enhances water–polymer interactions, which typically leads to an increase in the LCST (or TCP) of thermoresponsive polymers. However, in the present study, the LCST value is reported to decrease. The authors should clearly explain the underlying reason for this deviation and support their explanation with appropriate literature references where similar behavior has been reported.", "reviewer_2": "The manuscript of Pan et al. explores the use of PNIPAM as a matrix for tissue-adaptive fibers that exploit the thermoresponsive behavior of PNIPAM to enable self-tightening upon implantation. Overall, this is an elegant approach to implant soft-matter materials with a conductive interface in a reversible and adhesive manner. Additionally, the authors characterize the different aspects of the material, such as tensile strength, thermal, and electronic properties, necessary to support its function. Biocompatibility is also briefly shown. Although the overall approach is attractive, it is not unique; the authors need to clarify the specific novelty over other approaches, such as shape-memory electrodes or water-responsive films. Additionally, some of the claims, such as “ultrastable,” are not well-supported, and the overall discussion should be improved, namely, the obtained results should be placed into the broader context of neural interface materials.\nComment #1: In the introduction, the authors broadly cover the design rationale, highlighting the need for reversible, yet responsive materials to provide neural interfaces. However, the state of the art remains elusive to the reader, and the specific novelty of the presented work remains unclear. How does the authors’ approach differ from shape-memory electrodes (Sci. Adv., 5,eaaw1066(2019), Nat. Mater. 23, 969–976 (2024)) , water-responsive films as self-tightening bioelectronic interfaces (Nature 624, 295–302 (2023))? This needs to be clarified.\nComment #2: The authors assess the biocompatibility in vitro with mouse fibroblast, which shows negligible cytotoxicity. Additionally, the authors interface their materials with the sciatic nerve. While their results show no toxicity in vitro, it is important to note that this does not mean that the material is biocompatible. As mentioned in the introduction, some materials can cause inflammation, and therefore, I recommend that the authors perform histological assessments on the nerves to demonstrate the absence of inflammation and demonstrate the overall safety of the materials.\nComment#3: While the overall concept is elegant, the level of responsiveness remains unclear. In realistic application scenarios, the described shrinkage needs to occur fast, yet, the time scale at which the response takes place is not described. The manuscript would benefit from additional supplementary videos that demonstrate the time scale at which the responsiveness occurs in simulated implantation scenarios.\nComment#4: The authors claim that the reported neural interfaces are ultrastable, yet it remains unclear what is meant by ultrastable. In their report, there are no durability tests that report a durable performance of the material in an applicational setting. The term ultrastable in the context of neural interfaces would ideally imply durable and reproducible responses over the course of hours, or multiple days.\nComment #5: Throughout the manuscript, the characterization of the materials is predominantly reported to control materials of a similar composition to underline the need for the different components of the composite. Yet, the discussion of the results section would strongly benefit from the contextualization of these results versus other systems, such as state of the art hydrogel electrodes. This would enrich the overall discussion and more clearly indicate the overall novelty of the present work.\nComment #6: In several instances, the reporting of the results is incomplete. For the polymer preparation, dispersity and yield are missing, for the tensile strength, I assume the elongation at break are the represented percentages, not the tensile strength. For the animal experiments, it is unclear how many animals were included and what the overall variability of the responses was. These details need to be better represented in the manuscript to ensure the reproducibility and proper reporting of the results.", "reviewer_3": "Summary\nThe manuscript entitled “Tissue-adaptive bioelectronic fibers with temperature-induced self-tightening enable ultrastable neural interface” reports the development of thermoresponsive, self-tightening bioelectronic fibers composed of PNIPAm/SA/PPy@CNT. The authors demonstrate temperature-triggered self-contraction based on the LCST behavior of PNIPAm, enhanced tissue conformity, mechanical compliance, electrochemical performance, cytocompatibility, and in vivo sciatic nerve stimulation and signal recording in rats.\nOverall, the concept is intriguing and has potential significance for neural interface technologies. However, several issues hinder the clarity and completeness of the manuscript. In particular, the Introduction and Results sections contain overlapping or misplaced content; the scientific rationale behind demonstrations on organs other than the sciatic nerve is unclear; and safety considerations are insufficiently addressed. These issues collectively indicate the need for substantial revision.\nMajor Comments\n1. Mixing of Introduction and Results Content (Structural Issue)\nThe Introduction should clearly present the research background, existing challenges, and the position of this study, without including experimental results such as LCST values or mechanical modulus. Several parts of the manuscript inappropriately mix Introduction-like material into the Results section:\n- The conceptual illustration in Fig. 1 and demonstrations on various organs should be described in the Results, not the Introduction.\n- In the Results subsection “Fabrication and characterization of tissue-adaptive bioelectronic fibers,” the first paragraph (p.6) and the LCST explanations spanning p.7–8 redundantly repeat Introduction-level content.\n- Similarly, the first paragraph of the subsection “In vivo electrical stimulation and neural signal recording” is partly introductory and should be revised to suit the Results section.\nIn addition, the Introduction should more clearly describe:\n- the rationale for using thermoresponsive materials,\n- the significance of LCST behavior,\n- distinctions from prior literature, and\n- the specific challenges this work aims to address.\n2. Unclear Significance of Demonstrations on Non-sciatic Tissues\nFig. 1c shows demonstrations of the fiber wrapped around organs such as the kidney, muscle, and heart. While visually striking, their scientific or engineering significance is not adequately explained.\nThe authors should clarify:\n- Why these organs were chosen,\n- Whether tightening may pose compression risks,\n- Whether such use-cases are realistic in practical applications,\n- Whether the demonstrations are conceptual only or linked to envisioned functionalities.\nThese points should be addressed in the Discussion.\n3. Insufficient Consideration of Safety\nThe manuscript claims that the generated stress of about 3 kPa is not harmful; however, potential risks such as nerve compression, blood flow obstruction, or inflammatory responses are insufficiently discussed. In particular, if the authors wish to claim that the device “enables long-term neural monitoring,” they must support this statement with long-term inflammation data or relevant literature.\n4. Inadequate Discussion of Electrode Comparison (Fundamental Control Difference)\nSPC lacks PNIPAm and therefore does not exhibit thermoresponsive contraction. As a result, SPC cannot serve as a complete control for PSPC, since PSPC benefits from temperature-induced tightening and enhanced interface stability. The authors should explicitly acknowledge this limitation.\nFurthermore, comparison with conventional metal electrodes and recently reported high-performance hydrogel electrodes is insufficient. The manuscript would benefit from situating PSPC performance within the broader context of existing electrode technologies.\n5. Reproducibility and Transparency of In Vivo Experiments\n(1) Animal number (n) and variability\nThe number of rats used is not reported. If multiple animals were used, please specify:\n- the sample size (n),\n- variability in stimulation-induced limb angles,\n- variability in AP amplitude retention (e.g., SD).\n(2) Use of only 1 Hz in in vivo stimulation\nThe authors discuss electrode performance based on stimulation data at a single frequency (1 Hz). Because a single frequency is insufficient to assess stability comprehensively, the authors should either:\n- provide data across additional frequencies, or\n- justify why 1 Hz is representative.\n(3) Long-term monitoring claim\nWithout inflammation assessment or long-term interface stability data, the claim of enabling long-term neural monitoring is overstated. The authors should support this with experimental results or suitable citations.\nMinor Comments\n1. Clarification of LCST Determination\nPlease specify how the LCST was defined from the DSC endothermic peak and show correspondence with swelling/shrinking measurements.\n2. Terminology Consistency\nThe manuscript inconsistently uses “PSPC fiber” and “PSPC fibers.” Please unify the terminology.\n3. Editing for Clarity\nSome expressions in the Introduction and Discussion are verbose or difficult to follow. Careful language editing is recommended.\n4. Redundant SEM Images\nFig. 2f appears almost identical to Supplementary Fig. 2b. Consider removing one of them.\n5. Significant Figures\nThe CIC value (p.13, five lines from the bottom) is reported with four significant digits, inconsistent with other parameters. Please unify the notation.\nRecommendation\nMajor Revision\nThe study presents valuable concepts and results, but significant improvements are required. Reorganization of the manuscript, clarification of scientific rationale, reinforcement of safety considerations, and greater transparency in in vivo methodology will substantially enhance the clarity and impact of this work.", "reviewer_4": "This manuscript reports a tissue-adaptive bioelectronic fiber that autonomously conforms to rat sciatic nerves at physiological temperature, forming ultrastable neural interfaces for efficient neural stimulation and reliable recording of nerve action potentials. The thermoresponsive polymer and electroactive materials might be useful in developing a tissue-adaptive bioelectronic fiber. While the premise of this study is interesting, I feel that the manuscript suffers from significant issues regarding material characterization, physical interpretation, and experimental rigor.\nA primary concern is the characterization of the PPy coating. The amount of PPy on the CNT surface is a governing factor for the composite's performance, yet the authors have not quantified this accurately. Relying solely on changes in fiber diameter is far too indirect to be reliable, and it is entirely unclear how the film thickness was measured. Without precise quantification here, the subsequent discussion rests on shaky ground.\nRegarding mechanical properties, the increase in Young's modulus for the PSPC fiber (to 160 kPa) compared to the PS fiber is noted, but the material hardly seems robust. PNIPAm hydrogels are inherently weak and brittle, and the reported values do not suggest a breakthrough in strength. The authors attribute the slight reinforcement to \"interactions\" between the PPy@CNT and the polymer matrix, but fail to specify the nature of these interactions. Vague assertions about polymer-filler interactions are insufficient without experimental evidence clarifying the mechanism.\nThe discussion surrounding thermal properties is particularly problematic. The authors report a DSC transition at 26.7 °C as the \"LCST\" of the solid fiber. This terminology is incorrect; LCST describes a phase separation temperature for a polymer in solution (an equilibrium state), not a thermal event in a solid composite. Furthermore, the explanation that Ca ions lower this temperature by hindering hydrogen bonding is unconvincing. The text also conflates equilibrium thermodynamics with non-equilibrium factors—such as cross-linking density and water permeability—when attempting to explain the shift based on PPy@CNT dispersion. These concepts need to be disentangled.\nFinally, the practical application section raises questions about reproducibility. The method for wrapping the fiber around the nerve is not clearly described. While the authors credit thermal contraction for the tight fit, they overlook the role of surface chemistry: at higher temperatures, the polymer becomes hydrophobic, which likely aids adhesion to the tissue by excluding interfacial water. This mechanism should be considered alongside contraction. Most critically, Figure 5 appears to rely on a single experimental run (n=1). Unless the authors can provide statistical data from repeated trials, the reported utility of the device remains anecdotal rather than scientifically proven.\nIn conclusion, the concept of using a thermoresponsive polymer for temperature-induced self-tightening is indeed an original aspect of this work. However, this novelty does not extend to the other results presented; given the numerous methodological and interpretative flaws outlined above, I do not feel this paper provides sufficient beneficial information to warrant publication in Nature Communications. As a result, this manuscript does not meet the requirements of urgency and novelty that justify its publication in Nature Communications. I feel that this manuscript cannot provide insight into valuable information for developing tissue-adaptive bioelectronic fibers. I think that this manuscript does not meet the standards of Nature Communications. As a result, I do not recommend for this paper to be published in Nature Communications."}, "author_response": "Detailed responses to reviewers' comments\nResponse to Reviewer #1\nComment: I have thoroughly evaluated the manuscript entitled “Tissue-adaptive\nbioelectronic fibers with temperature-induced self-tightening enable ultrastable neural\ninterface” (Manuscript Number: NCOMMS-25-86621) submitted by Pan et al. Please\nfind below my comments and suggestions for improvement. The manuscript may be\nconsidered for publication after the revision.\nResponse: Thank you very much for your positive comments. The manuscript has been\ncarefully revised to address the concerns, and the point-by-point responses are provided\nbelow. The main revisions are highlighted in yellow in the revised manuscript.\nQ1. It is not evident whether the authors have evaluated the properties of the system in\nthe absence of CNTs. If such a comparison has not been performed, the authors are\nstrongly encouraged to investigate the properties of the fibers without CNTs to clearly\ndemonstrate the contribution of CNT incorporation. Moreover, the authors should\nclarify whether alternative nanotube (instead of CNTs) can be used in this system or\nnot.\nResponse: Thank you for your helpful suggestion. We compared the electrochemical\nperformance of fibers with and without CNT. The incorporation of CNT into fibers\nreduces the impedance at 1 kHz from 4370 Ω to 2227 Ω while increasing the charge\nstorage capacity from 0.65 to 0.84 mC cm-2 (Fig. R1). These results indicate that CNT\nincorporation improves the electrochemical performance of composite fibers. We have\nadded discussion and figures in the revised manuscript (Page 13, Paragraph 1; Page 14,\nParagraph 1; Supplementary Figs. 9 and 14).\nFig. R1 Comparison of impedance (a) and cyclic voltammograms (b) of\nPNIPAm/SA/PPy and PNIPAm/SA/PPy@CNT fibers.\nR1\nAs suggested, other nanomaterials, including silver nanowires (AgNW) and\npolyaniline (PANI) nanorods, were incorporated into the fibers to fabricate\nPNIPAm/SA/AgNW and PNIPAm/SA/PANI fibers. As shown in Supplementary Fig.\n12, the freshly prepared fibers exhibited similar impedance values. However, after\nimmersion in PBS, both PNIPAm/SA/PANI and PNIPAm/SA/AgNW fibers showed\nsignificant degradation in electrochemical performance. After 6 h of soaking, their\nimpedances increased to 11268 and 9845 Ω, respectively, whereas the CNT-containing\nfibers maintained a relatively low impedance of 2810 Ω. This degradation is attributed\nto PANI dedoping in PBS (pH: 7.4) and chloride-induced corrosion of AgNW. In\ncontrast, CNT-based fibers remained largely unchanged in electrochemical\nperformance under the same conditions, indicating good stability. We have added\ndiscussion, figures, and experimental details in the revised manuscript (Page 13,\nParagraph 1; Page 25, Paragraph 1; Supplementary Fig. 12).\nSupplementary Fig. 12 (a) Impedance spectrum of three types of fibers with different\nnanomaterials. (b) Impedance of the fibers at 1 kHz in PBS at 25 °C after different\nimmersion times. Data are presented as mean ± SD (n = 4).\nQ2. The authors should evaluate the stability of the fabricated fibers after immersion\nin PBS buffer over different time intervals. This will help understand their structural\nintegrity and suitability for potential applications.\nResponse: Thanks for your suggestion. The stability of the fibers was evaluated after\nimmersion in PBS for different time intervals. The results show that both the diameter\nand mass remain almost unchanged after 12 h in PBS solution at 37 °C, indicating good\nstructural stability of the fibers. We have added these data and corresponding\ndescription to the revised manuscript (Page 8; Supplementary Fig. 6).\nR2\nSupplementary Fig. 6. The mass and diameter changes of PSPC fibers during\nimmersion in PBS at 37 °C. Data are presented as mean ± SD (n = 4).\nQ3. Figure 3a and Figure 6 (SI) should be merged into a single plot to enable a clearer\nand more direct comparison. Additionally, the authors are encouraged to use an\nalternative method to validate the cloud-point temperature (TCP) and strengthen the\nreliability of the reported results.\nResponse: Thanks for your comment. As suggested, Figure 6 (SI) has been merged into\nFigure 3a. Rheological measurements were employed to evaluate the phase transition\nbehavior of the networks. The transition temperatures were determined to be 23.9 °C\nfor PNIPAm/SA and 26.7 °C for PNIPAm/SA/PPy@CNT (Fig. R2), which are in good\nagreement with those obtained from DSC.\nFig. R2 Temperature-dependent storage modulus of PNIPAm, PNIPAm/SA,\nPNIPAm/SA/CaCl , and PNIPAm/SA/PPy@CNT/CaCl .\n2 2\nQ4. In general, hydrophilic sodium/calcium alginate enhances water–polymer\ninteractions, which typically leads to an increase in the LCST (or TCP) of\nthermoresponsive polymers. However, in the present study, the LCST value is reported\nto decrease. The authors should clearly explain the underlying reason for this deviation\nand support their explanation with appropriate literature references where similar\nR3\nbehavior has been reported.\nResponse: Thank you for the comment. In our system, the presence of Ca2+ ions alters\nthe hydration behavior of the PNIPAm-based network through direct interactions with\nthe polymer chains. Specifically, Ca2+ ions coordinate with the amide oxygen atoms of\nPNIPAm, thereby limiting hydrogen bonding between PNIPAm and water molecules.\nConsequently, hydrophobic interactions among PNIPAm chains become more\npronounced, leading to chain contraction at lower temperatures and a corresponding\ndecrease in the phase transition temperature. This behavior is consistent with previous\nstudies showing that the introduction of salt ions reduces the phase transition\ntemperature of PNIPAm-based systems (Nat. Commun. 2024, 15, 3925; Adv. Funct.\nMater. 2025, doi.org/10.1002/adfm.202519482). We have added this clarification and\ncited the relevant references (Page 9; References 41 and 42).\nR4\nResponse to Reviewer #2\nComment: The manuscript of Pan et al. explores the use of PNIPAM as a matrix for\ntissue-adaptive fibers that exploit the thermoresponsive behavior of PNIPAM to enable\nself-tightening upon implantation. Overall, this is an elegant approach to implant soft-\nmatter materials with a conductive interface in a reversible and adhesive manner.\nAdditionally, the authors characterize the different aspects of the material, such as\ntensile strength, thermal, and electronic properties, necessary to support its function.\nBiocompatibility is also briefly shown. Although the overall approach is attractive, it is\nnot unique; the authors need to clarify the specific novelty over other approaches, such\nas shape-memory electrodes or water-responsive films. Additionally, some of the claims,\nsuch as “ultrastable,” are not well-supported, and the overall discussion should be\nimproved, namely, the obtained results should be placed into the broader context of\nneural interface materials.\nResponse: Thank you very much for your positive comments and valuable suggestions.\nWe are pleased that you find our work to present an elegant and attractive approach for\nimplantable soft-matter materials. The manuscript has been revised accordingly, with\nadditional experimental data and discussion included. The main changes are highlighted\nin yellow, and detailed point-by-point responses are provided below. We thank the\nreviewer again for the constructive comments, which have helped improve our work.\nQ1. In the introduction, the authors broadly cover the design rationale, highlighting\nthe need for reversible, yet responsive materials to provide neural interfaces. However,\nthe state of the art remains elusive to the reader, and the specific novelty of the presented\nwork remains unclear. How does the authors’ approach differ from shape-memory\nelectrodes (Sci. Adv., 5, eaaw1066(2019), Nat. Mater. 23, 969–976 (2024)), water-\nresponsive films as self-tightening bioelectronic interfaces (Nature 624, 295–302\n(2023))? This needs to be clarified.\nResponse: Thank you for your comments. We have revised the Introduction to provide\na clearer overview of the state-of-the-art, including a comparison of representative\nstudies and their limitations. The novelty and main contributions of this work are now\nclearly summarized at the end of the Introduction. These revisions can be found in the\nlast two paragraphs of the Introduction (Pages 4 and 5). We thank the reviewer for the\nvaluable and insightful guidance.\nQ2. The authors assess the biocompatibility in vitro with mouse fibroblast, which shows\nnegligible cytotoxicity. Additionally, the authors interface their materials with the\nR5\nsciatic nerve. While their results show no toxicity in vitro, it is important to note that\nthis does not mean that the material is biocompatible. As mentioned in the introduction,\nsome materials can cause inflammation, and therefore, I recommend that the authors\nperform histological assessments on the nerves to demonstrate the absence of\ninflammation and demonstrate the overall safety of the materials.\nResponse: Thank you for the comments. We have added histological analyses of tissues\nafter fiber implantation to evaluate biocompatibility. Specifically, the PSPC fiber was\nimplanted into the dorsal subcutaneous tissue of SD rats. Tissues from the implantation\nsites were subjected to hematoxylin and eosin (H&E), α-smooth muscle actin (α-SMA),\nand cluster of differentiation 68 (CD68) staining. As shown in new Figs. 5c-e, there are\nno significant macrophage aggregation, inflammatory responses, or fibrotic\nencapsulation around the implanted fiber compared with the sham-operated control\ngroup, indicating good biocompatibility of PSPC fibers. These data and the\ncorresponding description have been added to the revised manuscript (Page 16; Page\n27, Paragraph 3; Figs. 5c-e).\nFigs. 5c-e (c) H&E staining and immunofluorescence images of rat subcutaneous\ntissues after one week of PSPC fibers implantation (scale bar: 200 μm); the sham-\noperated samples served as the control group. (d, e) Normalized fluorescence intensity\nof fibroblasts (α-SMA) (d) and macrophages (CD68) (e) in rat subcutaneous tissues\nwith and without PSPC fibers implantation. Statistical significance and P values were\ndetermined by two-sided Student’s t-test. Data in (d) and (e) are presented as mean ±\nSD (n = 4). NS, not significant.\nQ3. While the overall concept is elegant, the level of responsiveness remains unclear.\nR6\nIn realistic application scenarios, the described shrinkage needs to occur fast, yet,\nthe time scale at which the response takes place is not described. The manuscript would\nbenefit from additional supplementary videos that demonstrate the time scale at which\nthe responsiveness occurs in simulated implantation scenarios.\nResponse: Thank you for the suggestion. As suggested, we constructed a simulated\nimplantation scenario to show the real-time responsiveness behavior. Specifically, a\nbioelectronic fiber was wrapped around a PDMS fiber and placed in a temperature-\ncontrolled chamber at 37 °C to mimic physiological temperature. The fiber rapidly\nunderwent self-adaptive contraction within 3 s, forming a stable and conformal\ninterface. A supplementary video and description have been added (Page 11;\nSupplementary Video 3).\nQ4. The authors claim that the reported neural interfaces are ultrastable, yet it remains\nunclear what is meant by ultrastable. In their report, there are no durability tests that\nreport a durable performance of the material in an applicational setting. The term\nultrastable in the context of neural interfaces would ideally imply durable and\nreproducible responses over the course of hours, or multiple days.\nResponse: Thank you for the comment and suggestion. Electrical stimulation of the\nsciatic nerve induces hindlimb muscle contractions, which in turn cause mechanical\nmotion of the nerve. Such motion makes it challenging to maintain a stable electrode-\nnerve interface. In this work, “ultrastable” refers to the ability of the fiber-nerve\ninterface to remain stable in the presence of stimulation-induced motion, thereby\nenabling highly consistent neural stimulation and signal recording.\nAs shown in Fig. 6c, during neural stimulation, PSPC fibers preserved the\nstimulation effects much better than the control SPC fibers. After multiple stimulations,\nthe responses induced by SPC fibers declined markedly, with the movement angle and\ntension force dropping to 25.5% and 35.2% of their initial values, respectively. In\ncontrast, PSPC fibers maintained stable responses with minimal variation (Figs. 6d, e).\nFurthermore, we performed additional experiments to evaluate the stability of the\nfiber-nerve interface. The results confirm stable performance over a longer period of\nthree hours and across different stimulation frequencies. Stable stimulation responses\nwere maintained under stimulations delivered at one-hour intervals (Supplementary Fig.\n25). These results demonstrate the excellent durability of the fiber-nerve interface. The\ncorresponding discussion and figures have been added to the revised manuscript.\nR7\nSupplementary Fig. 25 Time-dependent changes in hindlimb movement angle and\nmuscle tension induced by PSPC fibers at different stimulation frequencies, with (a) 1\nHz, (b) 3 Hz, and (c) 5 Hz. Data are represented as mean ± SD (n = 4 independent rats).\nFor neural signal recording, we further performed durability tests by increasing\nthe number of consecutively recorded evoked action potentials from 100 to 1000. The\nPSPC fiber still maintained a signal retention rate of up to 99.5%, providing further\nevidence for the ultrastable fiber-nerve interface (Fig. 6h).\nWe have added these new data and description in the revised manuscript (Page 18,\nParagraph 2; Page 19; Figs. 6d, e, and h; Supplementary Fig. 25). We thank the reviewer\nagain for the constructive suggestion that helped improve the quality of our manuscript.\nQ5. Throughout the manuscript, the characterization of the materials is predominantly\nreported to control materials of a similar composition to underline the need for the\ndifferent components of the composite. Yet, the discussion of the results section would\nstrongly benefit from the contextualization of these results versus other systems, such\nas state of the art hydrogel electrodes. This would enrich the overall discussion and\nmore clearly indicate the overall novelty of the present work.\nResponse: Thank you for this constructive comment. As suggested, we have expanded\nthe Results section to include a detailed comparison between the bioelectronic fibers\nand representative state-of-the-art electrodes. Supplementary Table 1 and its\ncorresponding description have been added to the last paragraph of the Result section\n(Last paragraph of Page 21 and the first paragraph of Page 22; Supplementary Table 1).\nQ6. In several instances, the reporting of the results is incomplete. For the polymer\npreparation, dispersity and yield are missing, for the tensile strength, I assume the\nelongation at break are the represented percentages, not the tensile strength. For the\nanimal experiments, it is unclear how many animals were included and what the overall\nvariability of the responses was. These details need to be better represented in the\nR8\nmanuscript to ensure the reproducibility and proper reporting of the results.\nResponse: Thank you for pointing out the incomplete reporting of the experimental\nresults. We have provided the missing information and clarified the relevant\ndescriptions. Specifically, the dispersity and yield of the polymer preparation have been\nadded. The descriptions of the mechanical properties have been revised for clarity, and\nthe number of animals (Page 28, Paragraph 2) and data variability have been included.\nWe have also carefully rechecked the manuscript to ensure that all experimental details\nare clearly and adequately reported. We thank the reviewer for these detailed and\nvaluable comments, which have improved our manuscript.\nR9\nResponse to Reviewer #3\nComment: The manuscript entitled “Tissue-adaptive bioelectronic fibers with\ntemperature-induced self-tightening enable ultrastable neural interface” reports the\ndevelopment of thermoresponsive, self-tightening bioelectronic fibers composed of\nPNIPAm/SA/PPy@CNT. The authors demonstrate temperature-triggered self-\ncontraction based on the LCST behavior of PNIPAm, enhanced tissue conformity,\nmechanical compliance, electrochemical performance, cytocompatibility, and in vivo\nsciatic nerve stimulation and signal recording in rats.\nOverall, the concept is intriguing and has potential significance for neural interface\ntechnologies. However, several issues hinder the clarity and completeness of the\nmanuscript. In particular, the Introduction and Results sections contain overlapping or\nmisplaced content; the scientific rationale behind demonstrations on organs other than\nthe sciatic nerve is unclear; and safety considerations are insufficiently addressed.\nThese issues collectively indicate the need for substantial revision.\nRecommendation\nMajor Revision\nThe study presents valuable concepts and results, but significant improvements are\nrequired. Reorganization of the manuscript, clarification of scientific rationale,\nreinforcement of safety considerations, and greater transparency in in vivo\nmethodology will substantially enhance the clarity and impact of this work.\nResponse: Thank you very much for your positive comments and valuable suggestions.\nWe have revised the manuscript to eliminate overlapping or misplaced content between\nthe Introduction and Results sections, and to clarify the scientific rationale for\ndemonstrations on organs other than the sciatic nerve. In addition, safety-related data\nand discussion have been added, and additional experimental details have been\nprovided. The manuscript has been carefully revised to address the concerns, with\npoint-by-point responses provided below. The main revisions are highlighted in yellow\nin the revised manuscript. Thank you again for your comments that significantly\nimprove our work.\nMajor Comments\nQ1. Mixing of Introduction and Results Content (Structural Issue)\nThe Introduction should clearly present the research background, existing challenges,\nand the position of this study, without including experimental results such as LCST\nvalues or mechanical modulus. Several parts of the manuscript inappropriately mix\nR10\nIntroduction-like material into the Results section:\n- The conceptual illustration in Fig. 1 and demonstrations on various organs should be\ndescribed in the Results, not the Introduction.\n- In the Results subsection “Fabrication and characterization of tissue-adaptive\nbioelectronic fibers,” the first paragraph (p.6) and the LCST explanations spanning\np.7–8 redundantly repeat Introduction-level content.\n- Similarly, the first paragraph of the subsection “In vivo electrical stimulation and\nneural signal recording” is partly introductory and should be revised to suit the Results\nsection.\nIn addition, the Introduction should more clearly describe:\n- the rationale for using thermoresponsive materials,\n- the significance of LCST behavior,\n- distinctions from prior literature, and\n- the specific challenges this work aims to address.\nResponse: Thank you for the valuable suggestion. We have carefully revised the\nmanuscript to clearly separate the Introduction and Results sections by relocating any\nmixed content to the appropriate sections. The specific revisions are as follows:\n(1) Experimental results, such as LCST values and mechanical modulus, been deleted\nfrom the Introduction. The conceptual illustration in Fig. 1 and the related\ndemonstrations on various organs have been moved from the Introduction to the\nResults section (Page 4, Paragraph 2; Page 5; Page 6, Paragraph 1).\n(2) The LCST explanation in the Results subsection “Fabrication and characterization\nof tissue-adaptive bioelectronic fibers” has been simplified and refocused on the\ninterpretation of the experimental results.\n(3) The first paragraph of the subsection “In vivo electrical stimulation and neural\nsignal recording” has been revised to remove introductory content and align with\nthe Results section (Page 17).\n(4) The Introduction has been revised to more clearly describe the rationale for using\nresponsive materials, distinctions from prior studies, and the specific challenges\naddressed in this work (Page 4, Paragraph 1).\nQ2. Unclear Significance of Demonstrations on Non-sciatic Tissues\nFig. 1c shows demonstrations of the fiber wrapped around organs such as the kidney,\nmuscle, and heart. While visually striking, their scientific or engineering significance\nis not adequately explained.\nThe authors should clarify:\n- Why these organs were chosen,\nR11\n- Whether tightening may pose compression risks,\n- Whether such use-cases are realistic in practical applications,\n- Whether the demonstrations are conceptual only or linked to envisioned\nfunctionalities.\nThese points should be addressed in the Discussion.\nResponse: Thank you for your comment. We apologize for not clearly stating the\nsignificance of the demonstrations on non-sciatic tissues. We have made the following\nrevisions to address these concerns:\n(1) The kidney, muscle, and heart were chosen to represent soft tissues with different\ngeometries and surface curvatures. These demonstrations are intended to show the\ngeometric adaptability and general conformability of the thermoresponsive fiber.\nThis purpose has been clarified in the revised manuscript (Page 6, Paragraph 1).\n(2) The potential risk of tissue compression has been evaluated. As shown in Fig. 3e,\nsimulations indicate that the thermally induced tightening generates a low\ninterfacial stress of ~3 kPa, far below the ~9 MPa stress level reported to damage\nthe rat sciatic nerve (J. Neurotrauma 2004, 21, 1652). This clarification and the\ncorresponding references have been incorporated into the revised manuscript (Page\n11; Reference 43).\n(3) The demonstrations on the kidney and heart are conceptual and intended to\nillustrate the self-adaptive tightening behavior of the bioelectronic fiber. Functional\nvalidation is focused on the sciatic nerve and muscle. In addition, we have added\nadditional experiments demonstrating the applicability of the self-tightening fiber\nfor stable electrophysiological recording at muscle interfaces (Page 21, Paragraph\n1; Supplementary Fig. 28).\nQ3. Insufficient Consideration of Safety\nThe manuscript claims that the generated stress of about 3 kPa is not harmful; however,\npotential risks such as nerve compression, blood flow obstruction, or inflammatory\nresponses are insufficiently discussed. In particular, if the authors wish to claim that\nthe device “enables long-term neural monitoring,” they must support this statement\nwith long-term inflammation data or relevant literature.\nResponse: Thank you for pointing out the insufficient consideration of safety.\nRelevant experiments and discussion have been added, as detailed below.\nAs suggested, to assess vascular safety, blood flow following PSPC implantation\nwas systematically evaluated using laser speckle contrast imaging. No statistically\nsignificant differences in blood flow were observed compared with the control group\nR12\nwithout sample implantation, as quantified by the relative blood flow index\n(Supplementary Fig. 8), indicating that PSPC implantation does not induce detectable\nblood flow obstruction. The results and corresponding descriptions are provided in the\nrevised manuscript (Page 11; Supplementary Fig. 8).\nSupplementary Fig. 8 (a) Photographs and laser speckle blood flow images of nerve\nsurfaces with and without PSPC fibers implantation. BF denotes blood flow (a.u.). (b)\nComparison of blood flow (a.u.) on the nerve surfaces with and without PSPC fibers\nimplantation. Statistical significance and P values were determined by two-sided\nStudent’s t-test, data are presented as mean ± SD (n = 4). NS, not significant.\nWe have added histological assessments of tissues after material implantation\nto evaluate biocompatibility. Specifically, the PSPC fiber was implanted into the dorsal\nsubcutaneous tissue of SD rats. Tissues from the implantation sites were subjected to\nhematoxylin and eosin (H&E), α-smooth muscle actin (α-SMA), and cluster of\ndifferentiation 68 (CD68) staining. As shown in new Figs. 5c-e, there are no significant\nmacrophage aggregation, inflammatory response, or fibrotic encapsulation around the\nimplanted fiber compared with the sham-operated control group, indicating good\nbiocompatibility of PSPC fibers. Moreover, to avoid potential ambiguity regarding\nlong-term neural monitoring, the relevant descriptions in the manuscript have been\nrevised accordingly. The results and corresponding descriptions are provided in the\nrevised manuscript (Page 16; Page 27, Paragraph 3; Figs. 5c-e).\nR13\nFigs. 5c-e (c) H&E staining and immunofluorescence images of rat subcutaneous\ntissues after one week of PSPC fibers implantation (scale bar: 200 μm); the sham-\noperated samples served as the control group. (d, e) Normalized fluorescence intensity\nof fibroblasts (α-SMA) (d) and macrophages (CD68) (e) in rat subcutaneous tissues\nwith and without PSPC fibers implantation. Statistical significance and P values were\ndetermined by two-sided Student’s t-test. Data in (d) and (e) are presented as mean ±\nSD (n = 4). NS, not significant.\nQ4. Inadequate Discussion of Electrode Comparison (Fundamental Control Difference)\nSPC lacks PNIPAm and therefore does not exhibit thermoresponsive contraction. As a\nresult, SPC cannot serve as a complete control for PSPC, since PSPC benefits from\ntemperature-induced tightening and enhanced interface stability. The authors should\nexplicitly acknowledge this limitation.\nFurthermore, comparison with conventional metal electrodes and recently reported\nhigh-performance hydrogel electrodes is insufficient. The manuscript would benefit\nfrom situating PSPC performance within the broader context of existing electrode\ntechnologies.\nResponse: Thank you for the comments. We agree with the reviewer that SPC is not a\ncomplete control for PSPC. The SPC was used as a non-contractile counterpart to\nhighlight the contribution of thermoresponsive contraction to interfacial stability. This\npoint has now been explicitly stated in the revised manuscript.\nAs suggested, we have added a more comprehensive comparison between the\nbioelectronic fibers and representative metal- and hydrogel-based electrodes, as\nsummarized in Supplementary Table 1 (Page 21, Paragraph 2, and Page 22, Paragraph\n1; Supplementary Table 1). Thanks again for the constructive suggestions that improved\nour manuscript\nR14\nQ5. Reproducibility and Transparency of In Vivo Experiments\n(1) Animal number (n) and variability\nThe number of rats used is not reported. If multiple animals were used, please specify:\n- the sample size (n),\n- variability in stimulation-induced limb angles,\n- variability in AP amplitude retention (e.g., SD).\n(2) Use of only 1 Hz in in vivo stimulation\nThe authors discuss electrode performance based on stimulation data at a single\nfrequency (1 Hz). Because a single frequency is insufficient to assess stability\ncomprehensively, the authors should either:\n- provide data across additional frequencies, or\n- justify why 1 Hz is representative.\n(3) Long-term monitoring claim\nWithout inflammation assessment or long-term interface stability data, the claim of\nenabling long-term neural monitoring is overstated. The authors should support this\nwith experimental results or suitable citations.\nResponse: Thank you for pointing out the insufficient experiment details of in vivo\nexperiments and the lack of inflammation assessment. We have included detailed\ninformation on animal numbers and data variability, conducted stimulation experiments\nusing different frequencies, and performed comprehensive assessments of\ninflammation, as detailed below.\n(1) Details regarding the number of animals used, as well as the variability in\nstimulation-induced hindlimb angles and action potential amplitude retention, have\nbeen added to the revised manuscript. The updated information is presented in new\nFig. 6 and the Methods section.\n(2) Additional stimulation data across a range of frequencies have been included and\nare presented in the new Supplementary Fig. 25.\nSupplementary Fig. 25 Time-dependent in hindlimb movement angle and muscle\nR15\ntension induced by PSPC fibers at different stimulation frequencies, with (a) 1 Hz,\n(b) 3 Hz, and (c) 5 Hz. Data are represented as mean ± SD (n = 4 independent rats).\n(3) We have added histological assessments of tissues after material implantation to\nevaluate biocompatibility. Hematoxylin and eosin (H&E), α-smooth muscle actin\n(α-SMA), and CD68 immunostaining were performed. The results showed no\ndetectable signs of inflammation, fibrotic encapsulation, or tissue damage\ncompared with control tissues, supporting the in vivo biocompatibility of the\nmaterials. In addition, to avoid overstatement, we have revised the manuscript to\nremove claims of “long-term” monitoring. The results and corresponding\ndescriptions are provided in the revised manuscript (Page 16; Figs. 5c-e). Thank\nyou for your valuable suggestion.\nMinor Comments\nMQ1. Clarification of LCST Determination\nPlease specify how the LCST was defined from the DSC endothermic peak and show\ncorrespondence with swelling/shrinking measurements.\nResponse: Thank you for the comments. In the previous version, LCST was used for\nsimplicity; however, this term is not strictly applicable here because it is defined for\nphase separation in polymer-solvent systems, whereas the system investigated is a\nphysical crosslinked polymer network. In the revised manuscript, we therefore use the\nterm volume phase transition temperature (VPTT) to describe the temperature at which\nthe polymer network undergoes a thermally induced volume phase transition. The\nVPTT was determined from DSC measurements and defined as the temperature\ncorresponding to the maximum of the endothermic peak. This temperature corresponds\nto the transition of the polymer network from a hydrated, swollen state to a contracted\nstate. We have added these clarifications in the revised manuscript. Moreover, the fiber\ndiameter was also measured as a function of temperature. The characteristic\ntemperature derived from the fiber diameter-temperature curve is in the range of 27-\n29 °C, corresponding to the region with the maximum slope (Fig. R3). This value is in\ngood agreement with the temperature obtained from the DSC experiments.\nR16\nFig. R3 Variation in the normalized PSPC fiber diameter as a function of temperature.\nMQ2. Terminology Consistency\nThe manuscript inconsistently uses “PSPC fiber” and “PSPC fibers.” Please unify the\nterminology.\nResponse: We have unified the terminology by consistently using “PSPC fibers”\nthroughout the manuscript. Thanks for your suggestion.\nMQ3. Editing for Clarity\nSome expressions in the Introduction and Discussion are verbose or difficult to follow.\nCareful language editing is recommended.\nResponse: The language of the manuscript has been carefully revised. Thank you.\nMQ4. Redundant SEM Images\nFig. 2f appears almost identical to Supplementary Fig. 2b. Consider removing one of\nthem.\nResponse: The caption of Fig. 2f in the previous version was incorrect. Fig. 2f actually\nshows the magnified cross-sectional view of the fiber. We have corrected the caption\naccordingly, and therefore this figure has been retained. Thank you for your comment.\nMQ5. Significant Figures\nThe CIC value (p.13, five lines from the bottom) is reported with four significant digits,\ninconsistent with other parameters. Please unify the notation.\nResponse: We thank the reviewer for the suggestion. The CIC value has been revised\nto ensure consistent use of significant digits.\nR17\nResponse to Reviewer #4\nComment: This manuscript reports a tissue-adaptive bioelectronic fiber that\nautonomously conforms to rat sciatic nerves at physiological temperature, forming\nultrastable neural interfaces for efficient neural stimulation and reliable recording of\nnerve action potentials. The thermoresponsive polymer and electroactive materials\nmight be useful in developing a tissue-adaptive bioelectronic fiber. While the premise\nof this study is interesting, I feel that the manuscript suffers from significant issues\nregarding material characterization, physical interpretation, and experimental rigor.\nResponse: We sincerely thank the reviewer for the positive assessment of the novelty\nand potential impact of our tissue-adaptive bioelectronic fiber. The concerns regarding\nmaterial characterization, physical interpretation, and experimental rigor are valuable,\nand we have carefully addressed them in accordance with your detailed comments.\nThese revisions have substantially improved the clarity and robustness of this work.\nPoint-by-point responses are provided below, and the main revisions are highlighted in\nyellow in the revised manuscript.\nQ1. A primary concern is the characterization of the PPy coating. The amount of PPy\non the CNT surface is a governing factor for the composite's performance, yet the\nauthors have not quantified this accurately. Relying solely on changes in fiber diameter\nis far too indirect to be reliable, and it is entirely unclear how the film thickness was\nmeasured. Without precise quantification here, the subsequent discussion rests on shaky\nground.\nResponse: Thank you for the comment. The PPy content was quantitatively determined;\nhowever, the description in the previous version was not sufficiently clear, which may\nhave led to confusion. SEM analysis was used to examine the morphology and provide\nsemi-quantitative evidence of PPy deposition. We agree that the description of the fiber\ndiameter was not sufficiently rigorous, and we have removed it from the manuscript.\nThe PPy content in the PPy@CNT composites was quantitatively determined by\nweighing the CNT before and after the polymerization of pyrrole. The samples are\ndenoted as PPy @CNT , where x and y represent the mass ratio of PPy to CNT,\nx y\nrespectively. These details have now been updated in discussion and the Methods\nsection (Page 7, Paragraph 1; Page 24, Paragraph 2). We thank the reviewer for pointing\nthis out, which has helped us clarify the experimental details in the revised manuscript.\nQ2. Regarding mechanical properties, the increase in Young's modulus for the PSPC\nfiber (to 160 kPa) compared to the PS fiber is noted, but the material hardly seems\nR18\nrobust. PNIPAm hydrogels are inherently weak and brittle, and the reported values do\nnot suggest a breakthrough in strength. The authors attribute the slight reinforcement\nto \"interactions\" between the PPy@CNT and the polymer matrix, but fail to specify the\nnature of these interactions. Vague assertions about polymer-filler interactions are\ninsufficient without experimental evidence clarifying the mechanism.\nResponse: Thank you for the comment and suggestion. We agree that the Young’s\nmodulus of the PSPC fibers remains within the typical range of PNIPAm-based\nhydrogels and does not represent a breakthrough in strength. The increase from 60 to\n160 kPa indicates a moderate reinforcement, and the statement has been revised\naccordingly. This mechanical reinforcement is attributed to strengthened hydrogen-\nbonding interactions within PSPC fibers, particularly between PNIPAm and PPy@CNT,\nas evidenced by FTIR spectroscopy. The corresponding detailed discussion and\nreferences have been added to the revised manuscript (Page 7, Paragraph 2; Page 8;\nSupplementary Fig. 5; References 37 and 38).\nQ3. The discussion surrounding thermal properties is particularly problematic. The\nauthors report a DSC transition at 26.7 °C as the \"LCST\" of the solid fiber. This\nterminology is incorrect; LCST describes a phase separation temperature for a polymer\nin solution (an equilibrium state), not a thermal event in a solid composite. Furthermore,\nthe explanation that Ca ions lower this temperature by hindering hydrogen bonding is\nunconvincing. The text also conflates equilibrium thermodynamics with non-\nequilibrium factors—such as cross-linking density and water permeability—when\nattempting to explain the shift based on PPy@CNT dispersion. These concepts need to\nbe disentangled.\nResponse: Thank you for your valuable suggestion and correction. We agree that LCST\nis not an appropriate term for describing a thermal transition observed in a hydrogel\nfiber. We have therefore revised the description and now refer to this event as a volume\nphase transition temperature (VPTT).\nThe incorporation of Ca2+ ions alters the hydration state of the PNIPAm network\nthrough coordination with the carbonyl oxygen atoms of the amide groups, which\nweakens hydrogen bonding between PNIPAm and water. The resulting reduction in\nhydration promotes hydrophobic interactions among PNIPAm chains, causing polymer\nchain contraction at lower temperatures and leading to a downward shift of the\ntransition temperature. These observations are consistent with previous reports showing\nthat the presence of salt ions reduces the transition temperature of PNIPAm-based\nsystems (Nat. Commun. 2024, 15, 3925; Adv. Funct. Mater. 2025,\nR19\ndoi.org/10.1002/adfm.202519482). Relevant explanations and references have been\nadded in the revised manuscript (Page 9; References 41 and 42).\nWe have clarified that the transition temperature of the PNIPAm-based system is\nprimarily determined by polymer-water interactions. Meanwhile, PPy@CNT promotes\nhydrogen-bonding interactions with the PNIPAm/SA matrix, enhancing water retention\nwithin the polymer network. The corresponding discussion has been revised to\ndisentangle these concepts and improve clarity (Page 9).\nQ4. Finally, the practical application section raises questions about reproducibility.\nThe method for wrapping the fiber around the nerve is not clearly described. While the\nauthors credit thermal contraction for the tight fit, they overlook the role of surface\nchemistry: at higher temperatures, the polymer becomes hydrophobic, which likely aids\nadhesion to the tissue by excluding interfacial water. This mechanism should be\nconsidered alongside contraction. Most critically, Figure 5 appears to rely on a single\nexperimental run (n=1). Unless the authors can provide statistical data from repeated\ntrials, the reported utility of the device remains anecdotal rather than scientifically\nproven.\nResponse: Thank you for the comment. We have added a description of the fiber-\nwrapping procedure in the Methods section. Specifically, after surgical exposure of the\nnerve, the bioelectronic fiber was gently positioned alongside the nerve and manually\nguided with fine forceps to be wound around the nerve, forming three to five closely\nspaced turns.\nRegarding the role of surface chemistry, the polymer in the bioelectronic fiber\nbecomes more hydrophobic at physiological temperature and undergoes dehydration.\nThe expelled water originates from the interior of the fiber and is released to the exterior\nat the fiber-nerve interface. Meanwhile, the interface between the fiber and the nerve\nremains wet due to the intrinsically moist tissue surface. Therefore, the temperature-\ninduced contraction of the fiber plays a key role in achieving tight contact.\nThe experiments presented in the previous Fig. 5 and the related experiments in\nthe Supplementary Information been repeated in multiple independent trials. The\nrevised figure now shows the results as mean ± SD (Fig. 6; Supplementary Figs. 25-\n27). Thank you for the suggestion.\nQ5. In conclusion, the concept of using a thermoresponsive polymer for temperature-\ninduced self-tightening is indeed an original aspect of this work. However, this novelty\ndoes not extend to the other results presented; given the numerous methodological and\nR20\ninterpretative flaws outlined above, I do not feel this paper provides sufficient beneficial\ninformation to warrant publication in Nature Communications. As a result, this\nmanuscript does not meet the requirements of urgency and novelty that justify its\npublication in Nature Communications. I feel that this manuscript cannot provide\ninsight into valuable information for developing tissue-adaptive bioelectronic fibers. I\nthink that this manuscript does not meet the standards of Nature Communications. As\na result, I do not recommend for this paper to be published in Nature Communications.\nResponse: We appreciate the reviewer's positive comment on the novelty of the\ntemperature-induced self-tightening concept. As suggested, we have added additional\nexperiments to broaden the applicability of this functionality. The experiment\ndemonstrates the applicability of the self-tightening fiber for stable electrophysiological\nrecording at muscle interfaces, beyond neural interfaces.\nSpecifically, PSPC fibers were used to record compound muscle action potentials\n(CMAP) evoked by electrical stimulation. As shown in the new Supplementary Fig. 28,\nthree PSPC fibers were wound around the rat extensor digitorum longus muscle and\nserved as the recording, reference, and ground electrodes. For comparison, SPC fibers\nwithout the self-tightening function were used as a control. During electrical\nstimulation of the sciatic nerve, the resulting CMAP were recorded from the muscle.\nThe PSPC fibers maintained stable signals over a 3 h period, retaining more than 99%\nof the signal despite stimulation-induced muscle vibration. In contrast, signals recorded\nwith SPC fibers gradually deteriorated over time, with only 34.2 % signal retention.\nThis stability is attributed to the self-adaptive conformal contact between the PSPC\nfibers and the muscle tissue. These results demonstrate that the temperature-induced\nself-tightening electronic fiber enables a robust electrode-muscle interface for\nelectrophysiological signal recording. We have added discussion, figures, and\nexperimental details in the revised manuscript (Page 21, Paragraph 1; Page 28,\nParagraph 2; Supplementary Fig. 28).\nSupplementary Fig. 28 PSPC fibers for muscle action potential recording. (a)\nR21\nSchematic illustration of CMAP recording with three fibers wound around the EDL as\nrecording (Rec), reference (Ref), and ground (GND) electrodes, together with an optical\nimage of the conformally wound around PSCP fibers. (b) Comparison of CMAP signals\nrecorded from PSPC and PSP fibers at different time points, with electrical stimulation\napplied at each time point (300 μA, 0.5 Hz). (c) Comparison of CMAP signal retention\nfrom PSPC and PSP fibers at different time points. Data are presented as mean ± SD (n\n= 4).\nMoreover, we have added a more comprehensive comparison between our\nbioelectronic fibers and representative metal- and hydrogel-based electrodes to clarify\nthe distinctive features and contributions of the present work. The corresponding\ndiscussion and table have been included in the revised manuscript (Page 21, Paragraph\n2, and Page 22, Paragraph 1; Supplementary Table 1).\nSupplementary Table 1. Comparison of PSPC fibers with other electrodes used for\naction potential recording.\nR22\nDetailed responses to reviewers' comments\nReviewer #1\nComment: The issues raised have been adequately addressed in the revised manuscript\nentitled “Tissue-adaptive bioelectronic fibers with temperature-induced self-tightening\nenable ultrastable neural interface” (Manuscript Number: NCOMMS-25-86621A)\nsubmitted by Pan et al., and I believe that the revised manuscript is suitable for\npublication in Nature Communications.\nResponse: Thank you for your positive comments and recommendation for publication.\nReviewer #2\nComment: The authors have performed additional experiments and substantial\nrevisions to the manuscript in order to address the reviewer comments. Here,\nhighlighted issues such as reporting inconsitencies or incompleteness, were addressed\nby the authors, supporting the overall soundness of the methodology and the\nreproducibility of the presented work. As a result, the quality of the manuscript has\nimproved substantially, and it is close to publication. For the full appreciation of the\nnovelty and impact of the work by the readership of Nature Comm., I recommend the\nauthors to improve the manuscript text in the following areas:\nResponse: Thank you for your positive comments and for the recommendation\nregarding publication. We have revised the manuscript accordingly to better highlight\nthe novelty and broaden the impact of our work.\nQ1: The current introduction is mainly written from a materials perspective, but is\ncurrently lacking a perspective covering the clinical need and translational relevance.\nFor instance, the authors mention risk of inflammation and mechanical damage, and\nlater highlight loss of contact leading to loss of function. However, these issues are\ndescribed only in general terms and not sufficiently linked to clinically meaningful\nconsequences or unmet needs in neuromodulation. I recommend that the authors\nstrengthen the clinical motivation by clarifying why the interface instability is an\nimportant practical limitation, and what its clinical implications are. Where possible,\nthis should be supported by relevant literature (including clinically significant\ncomplication and intervention rates).\nResponse: Thank you for your suggestion. We have added discussion of the clinical\nmotivation in the Introduction, highlighting the limitations of interface instability in\nneuromodulation and its clinical implications. Relevant references have also been\nincluded.\nR1\nQ2: The authors have now included a comparative table of relevant reported\ntechnologies in this field to provide a better context for the obtained results. While this\nis certainly appreciated, the placement of the related text in the result section is\nunfortunate, and better suited for a discussion section. Additionally, the current\ndiscussion section remains poor and is simply a descriptive summary of the obtained\nresults, lacking the proper interpretation, contextualization, positioning, and\ndiscussion of limitations and future directions. I recommend that the authors\noverhaul the current discussion section in order better discuss the novelty and impact of\nthe presented technology in relation to competing technologies. Ideally, the authors\ndiscuss the following points in the discussion section:\nA) the relevance and motivation of the research\nB) highlight the conceptual and technical innovations of their research\nC) Discuss how the experiments supported the suitability for the intended application(s)\n(e.g. modularity of tissue interfacing, biocompatibility, mechanical adaptation,\nreversibility, durability, and generalizability)\nD) Benchmark these advances against literature, i.e. what has been specifically\nachieved or improved. E) Acknowledge limitations of the study and outline future\nimportant steps.\nSuch a revision would significantly strengthen the manuscript and emphasize the\nrelevance and impact of the presented bioelectronic fibers for readers in a fair and\ntransparent manner.\nResponse: We have revised the Discussion by incorporating relevant content from the\nResults and further expanding it as suggested. Many thanks for your suggestion.\nReviewer #3\nComment: I have carefully checked the revised manuscript and the authors' point-by-\npoint responses to the comments raised in the previous round of review. In my initial\nassessment, I identified a number of substantial concerns and therefore recommended\nrejection. However, in the present revised version, the authors have addressed those\nconcerns satisfactorily and have made appropriate revisions throughout the manuscript.\nIn particular, the responses to the major issues raised in the first review are clear,\nreasonable, and adequately supported by the revised text. As a result, I believe that the\nscientific quality and overall presentation of the manuscript have been improved to a\nlevel suitable for publication.\nTherefore, I now recommend acceptance of this manuscript in its present form, without\nany further revisions.\nResponse: Thank you for your positive comments and recommendation for publication.\nR2\nReviewer #4\nComment: The authors have carefully and thoroughly addressed my major concerns\nraised in the previous round of review.\nIn particular:\n1. Manuscript structure has been substantially improved.\nThe Introduction and Results sections are now clearly separated, and previously\noverlapping or misplaced content has been appropriately reorganized. The overall\nnarrative is significantly clearer and more logically structured.\n2. The scientific rationale has been clarified.\nThe demonstrations on non-sciatic tissues are now properly contextualized as\nillustrations of geometric adaptability, and the functional validation is appropriately\nfocused on neural and muscle interfaces.\n3. Safety considerations have been strengthened.\nThe authors have added vascular blood flow measurements and histological analyses\n(H&E, α-SMA, CD68), which show no detectable inflammatory response or tissue\ndamage at the one-week time point. Importantly, overstated claims regarding “long-\nterm monitoring” have been revised.\n4. Reproducibility and transparency have improved.\nAnimal numbers (n = 4) and variability are now clearly reported, additional stimulation\nfrequencies have been evaluated, and durability tests have been added.\n5. Control limitations have been acknowledged.\nThe authors explicitly recognize that SPC is not a complete control and provide broader\ncomparisons with state-of-the-art electrodes.\nOverall, the revised manuscript demonstrates substantial improvement in clarity, rigor,\nand completeness. While longer-term in vivo data would further strengthen the study,\nsuch data are not essential for supporting the present claims, which are now\nappropriately framed.\nIn my opinion, the authors have satisfactorily addressed the concerns raised in the\nprevious review, and the manuscript now meets the standards for publication in Nature\nCommunications.\nI recommend acceptance.\nResponse: Thank you for your positive comments and recommendation for publication.\nR3\nTo, Date: 22/02/2026\nThe Editor,\nNature Communications,\nDear Sir,\nThe issues raised have been adequately addressed in the revised manuscript entitled “Tissue-\nadaptive bioelectronic fibers with temperature-induced self-tightening enable ultrastable\nneural interface” (Manuscript Number: NCOMMS-25-86621A) submitted by Pan et al., and I\nbelieve that the revised manuscript is suitable for publication in Nature Communications.\nWith best regards\nSamarendra"}]

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