<figure><img src="image_34.png" /></figure>

<figure><img src="image_35.png" /><figcaption>**Fig. 13** Phase-sensitive hetero-metasurface-based biosensor using Goos–Hänchen effect. (a) Schematic presentation of a large lateral position shift induced by the Goos–Hänchen effect; (b) schematic of hetero-metasurface substrate based on Ge₂Sb₂Te₅ (GST) layers on a gold film (upper inset). Simulated angular dependence of G–H shift. The value of the shift reached 2107 µm at the resonant angle, which is much larger than the relevant value for a pure gold film in the SPR geometry (lower inset); (c) G–H shifts for GST-coated and uncoated Au substrates after the injection of glycerol solutions with different RI; (d) detection of 1 fM concentration of cancer marker TNF-α using 2D GST-on-Au substrate. Adapted from ref. 132 with permission from Springer Nature, copyright 2021.</figcaption></figure>

could reach 10⁵–10⁶ λ RIU⁻¹. G–H shifts can be also greatly enhanced in nanostructured metamaterials that enable the light darkness phenomenon. A variety of such metamaterials were recently proposed, including a nanophotonic asymmetric Fabry–Perot cavity near Brewster's angle,¹⁷⁷ a multi-layer hyperbolic metasurface⁶² or a metasurface with a nanogroove structure,¹⁶⁶ symmetric metal cladding plasmonic waveguide (SMCW) structures,¹⁰⁵ a subwavelength grating metamaterial (SGM) waveguide,¹⁷⁸ etc. The reported G–H shifts and sensitivities for nanoscale metamaterials roughly correspond to the relevant parameters obtained with their hetero-metasurface counterparts, suggesting that the presence of light darkness is a key parameter to achieve extreme sensitivity based on the G–H effect and this result can be achieved *via* the use of both hetero-metastuctures and nanostructured metamaterials.

Optical biosensors based on G–H shifts have already been tested in biomedical tasks and demonstrated high efficiency. In particular, using hetero-metasurface substrate based on GST layers on a gold film, Wang *et al*.¹³² reported the possibility of detection of sub-attomole concentrations of for TNF-α cancer marker (Fig. 13d), which is orders of magnitude lower than

LOD values obtained with their amplitude-sensitive counterparts. As another example, using silver-stibnite nanoporous plasmonic films, Sreekanth *et al*.¹⁷⁹ reported a LOD for the bovine serum albumin (BSA) molecule at level of 0.1 × 10⁻¹⁸ M, which corresponds to a submolecular detection level (0.13 BSA mm⁻²).

In general, detection schemes based on the G–H effect have demonstrated a high efficiency in extracting the phase-sensitive response in conditions of light darkness and could be applied for most structural layouts and metamaterial architectures described in the previous sections. One potential advantage is the relative simplicity and compactness of the experimental arrangement for the control of G–H shifts.

# 8. Recent advances

## 8.1 Dielectric platforms for optical label-free biosensing

Plasmonics provides an excellent platform for concentrating light in nanoscale with promising applications in biosensing and biomedicine. Recently, however, high-refractive index
Review Article

<figure><img src="image_37.png" /></figure>

dielectric nanostructures featuring low-loss resonances have been proposed as a encouraging alternative to nanoplasmonics, potentially offering comparable or even better sensing performances.<sup>180-182</sup> According to the Mie theory,<sup>183</sup> both plasmonic and dielectric particles can possess strong scattering resonances. Due to a low level of losses in dielectrics, high-index dielectric nanoparticles of simple geometries can exhibit the electric dipole (ED) and magnetic dipole (MD) resonances of comparable strengths (Fig. 14a and b). The enhancement of MD resonances occurs when the wavelength of light inside a

dielectric particle becomes comparable with the particle size. This condition can be achieved under $2R \approx \lambda/n$, where n is the refractive index of the dielectric nanoparticle, R is its radius, and $\lambda$ is wavelength of light.<sup>180-182</sup> Moreover, for larger nanoparticles, the MD resonance becomes stronger than the ED resonance providing a major contribution to the scattering efficiency. The spectral positions of both electric and magnetic dipole resonances can be tuned independently by changing the geometrical parameters of dielectric structures; e.g., Fig. 14a displays the spectral overlapping of MD and ED resonances for Si nanodiscs.

<figure><img src="image_38.png" /><figcaption>**Fig. 14** Dielectric platforms for label-free optical biosensing: (a) excitation of Mie resonances. Scattering cross section of a silicon (Si) nanodisc (200 nm radius and 260 nm height). Resonances related to magnetic and electric dipoles are denoted as MD and ED, respectively; (b) configuration of fields corresponding to resonant contributions from MD and ED in Panel (a). Adapted from ref. 182 with permission from American Chemical Society, copyright 2017; (c)–(f) dielectric metagrating platform for biosensing. (c) Schematic of operation of sensor based on periodically repeated 9-nanodisk unit cells (an example of such a cell is highlighted by red dashed line) and that of signal acquisition based on the control of diffraction intensity ratio $DIR = I_{-1}/I_0$ as a function of RI; (d) an image of a metagrating providing a small deflection angle (SDA); (e) light transmission spectra for different diffraction orders for the SDA grating shown in panel (d); (f) biosensing experiments on anti-Mouse Immunoglobulin G (IgG) detection. Schematic of selective binding of anti-Mouse IgG (upper inset). Dependence of average intensity ratio (DIR) on concentration of anti-Mouse IgG in the solution (range of concentrations from $5 \times 10^{-10}$ to $5 \times 10^{-2}$ mg mL$^{-1}$). The red curve shows a four-parameter logistic fit. Adapted from ref. 187 with permission from John Wiley and Sons, copyright 2022.</figcaption></figure>
Review Article

<figure><img src="image_36.png" /></figure>

dielectric nanostructures featuring low-loss resonances have been proposed as an encouraging alternative to nanoplasmonics, potentially offering comparable or even better sensing performances.<sup>180-182</sup> According to the Mie theory,<sup>183</sup> both plasmonic and dielectric particles can possess strong scattering resonances. Due to a low level of losses in dielectrics, high-index dielectric nanoparticles of simple geometries can exhibit the electric dipole (ED) and magnetic dipole (MD) resonances of comparable strengths (Fig. 14a and b). The enhancement of MD resonances occurs when the wavelength of light inside a

dielectric particle becomes comparable with the particle size. This condition can be achieved under $2R \approx \lambda/n$, where n is the refractive index of the dielectric nanoparticle, R is its radius, and $\lambda$ is wavelength of light.<sup>180-182</sup> Moreover, for larger nanoparticles, the MD resonance becomes stronger than the ED resonance providing a major contribution to the scattering efficiency. The spectral positions of both electric and magnetic dipole resonances can be tuned independently by changing the geometrical parameters of dielectric structures; e.g., Fig. 14a displays the spectral overlapping of MD and ED resonances for Si nanodiscs.

<figure><img src="image_37.png" /><figcaption>**Fig. 14** Dielectric platforms for label-free optical biosensing: (a) excitation of Mie resonances. Scattering cross section of a silicon (Si) nanodisc (200 nm radius and 260 nm height). Resonances related to magnetic and electric dipoles are denoted as MD and ED, respectively; (b) configuration of fields corresponding to resonant contributions from MD and ED in Panel (a). Adapted from ref. 182 with permission from American Chemical Society, copyright 2017; (c)–(f) dielectric metagrating platform for biosensing. (c) Schematic of operation of sensor based on periodically repeated 9-nanodisk unit cells (an example of such a cell is highlighted by red dashed line) and that of signal acquisition based on the control of diffraction intensity ratio $DIR = I_{-1}/I_0$ as a function of RI; (d) an image of a metagrating providing a small deflection angle (SDA); (e) light transmission spectra for different diffraction orders for the SDA grating shown in panel (d); (f) biosensing experiments on anti-Mouse Immunoglobulin G (IgG) detection. Schematic of selective binding of anti-Mouse IgG (upper inset). Dependence of average intensity ratio (DIR) on concentration of anti-Mouse IgG in the solution (range of concentrations from $5 \times 10^{-10}$ to $5 \times 10^{-2}$ mg mL$^{-1}$). The red curve shows a four-parameter logistic fit. Adapted from ref. 187 with permission from John Wiley and Sons, copyright 2022.</figcaption></figure>
<figure><img src="image_39.png" /></figure>

Recently, dielectric structures and their resonances (MD in particular) were successfully used in dielectric platforms for sensitive label-free optical biosensing. As an example, a low concentration of streptavidin was detected with the help of all-dielectric nanoresonators.<sup>184</sup> In this study, the authors validated a new dielectric sensing platform based on silicon nanodisks with strong optically induced MD resonances, which yielded a detection limit of streptavidin at the level of 5 ng mL<sup>-1</sup>. Yavas et al.<sup>185</sup> improved sensitivity of dielectric nanostructures by integrating arrays of antibody-functionalized silicon nanoresonators with microfluidics and demonstrated the detection of ~1 ng mL<sup>-1</sup> prostate specific antigen (PSA) in buffer. The sensing performance of dielectric Si nanodisks (a metasurface) was compared with that of gold nanorod arrays in a review article.<sup>186</sup> The authors showed that the dielectric metasurface possesses a better LOD compared to the plasmonic counterpart while the plasmonic nanorod metasurfaces afford a wider dynamic range.

Aoni et al.<sup>187</sup> proposed a dielectric metagrating platform for label-free optical biosensing based on an array of dielectric nanodiscs of different sizes, exhibiting individual Mie resonances. The nanodiscs were arranged in such a way that they could condition phase values from 0 to 2π in light transmitted through the structure (Fig. 14c). The whole structure presented a set of periodically repeated unit cells (highlighted by a dashed red line) to form a metagrating. The illumination of this structure by white light leads to the appearance of different diffraction orders in transmission and the intensity in these orders is conditioned by the phase ramp imprinted by the metagrating. It is critically important that under such a geometry the diffraction intensity ratio DIR = *I*<sub>-1</sub>*I*<sub>0</sub> (where *I*<sub>-1</sub> and *I*<sub>0</sub> are intensities in high and zero orders, respectively) becomes highly sensitive to RI of the medium contacting the structure (Fig. 14c, right panel), which opens up access to the employment of such megagratings to control biological binding events. Depending on metagrating parameter, the structure can provide large or small deflection angles. The authors showed that smaller deflection angle (SDA) metagratings can provide better sensitive response to RI variations. An example of such SDA grating and corresponding transition spectra from different diffraction orders are shown in Fig. 14d and e. Fig. 14f (upper inset) displays the immobilisation of a primary antibody (Mouse IgG) onto a dielectric metagrating using silicon to amine/sulfhydryl coupling strategy. Testing of the sensitivity was performed with the help of an anti-Mouse IgG binding assay by measuring the diffraction intensity ratio of the 0th and -1st diffraction orders at a range of analyte concentrations from 5 × 10<sup>-10</sup> to 5 × 10<sup>-2</sup> mg mL<sup>-1</sup>, Fig. 14f. The resulting LOD of 0.1 ng mL<sup>-1</sup> for anti-Mouse IgG was achieved.<sup>187</sup>

We briefly mention that in addition to reflection/transmis-
sion/diffraction techniques, the fluorescence (FL) detection can
be used in combination with dielectric metasurfaces.<sup>188,189</sup>
Iwanaga et al.<sup>188</sup> suggested to employ dielectric metasurface
FL sensors for the detection of COVID-19 spike protein. The
enhanced intensity of FL allowed one to measure the glyco-
proteins and antibodies more efficiently, as compared to other

methods previously reported. The FL sensors based on a di-
electric metasurface demonstrated LOD less than 0.64 pg mL⁻¹
for glycoprotein peptides detection and the dynamic range was
more than five orders of the target concentrations.¹⁸⁸ The
highest-sensitivity biosensing FL platform was demonstrated
in ref. 189, where immunoglobulin G with concentrations of
the order of pg mL⁻¹ was detected.

Some efforts on developing the dielectric platform for biosensing were discussed in a recent review.¹⁹⁰ It is worth stressing that, despite being impressive, LODs achieved with dielectric metasurfaces and other dielectric platforms (~1 ng mL⁻¹) are well below LODs that one can achieve with plasmonic phase metamaterials (~1 fg mL⁻¹), see Fig. 2. This means that the dielectric platform could probably be further improved by employing phase as the sensing parameter at the condition of light darkness.

8.2 The concept of bound states in the continuum for highly sensitive biosensors

High-index all-dielectric metasurfaces have a disadvantage of a broad spectral response at ED and MD resonances severely restricting their LOD. It was recently found that sharp resonances could be achieved by utilising the concept of bound states in the continuum (BICs). Narrow resonances in BICs happen when light waves remain completely localized at a metasurface even though they coexist with a continuous electromagnetic spectrum of the environment.<sup>192,193</sup> While original BICs suggested by von Neumann and Wigner<sup>194</sup> are difficult to implement, there are other practical scenarios leading to the generation of BICs. For example, BICs can be realised in Fabry-Perot structures, coupled resonances (Friedrich-Wintgen (FW) BICs), parametric structures, etc.<sup>192</sup> Usually, BICs possess very high (theoretically divergent, but finite) values of the quality factor (Q) due to structural losses and imperfections.

An application of quasi-BIC resonances for biosensing was demonstrated in metasurfaces based on a dimer-type unit cell.<sup>195</sup> The authors performed real-time in-flow detection of biological extracellular vesicles (EVs) secreted from cancer cells with the help of an immunoassay. A quasi-BIC metasurface was integrated with a microfluidic flow channel resulting in the overall LOD of 126 ng mL<sup>-1</sup>.<sup>195</sup> Wu et al.<sup>196</sup> implemented a BIC-based biosensor using a compound grating waveguide structure with a switchable guided resonance. Due to a high Q-factor of ~7000, such a sensor provided LOD of the sucrose concentration at the level of 1.6 × 10<sup>-5</sup> g mL<sup>-1</sup>. An optical biosensor with a high quality factor, Q was engineered using the Friedrich-Wintgen type BICs.<sup>197</sup> This sensor is valuable in quality control analysis of food processing, for example for trace detection of a specific benchmark analyte, ochratoxyn A. Experimentally, a relatively low LOD of 2.3 pg mL<sup>-1</sup> was achieved. In addition, a FW-BIC type biosensor could be applied for the detection of other mycotoxins and low-molecular weight molecules. The topological light confinement effect in a quasi-BIC resonator was employed for PNA/DNA selective biosensing with real-time monitoring of binding events.<sup>198</sup> Measurements of transmittance spectra before and after the incubation with c-DNA (c = 0.05 nM)
<figure><img src="image_38.png" /></figure>

Recently, dielectric structures and their resonances (MD in particular) were successfully used in dielectric platforms for sensitive label-free optical biosensing. As an example, a low concentration of streptavidin was detected with the help of all-dielectric nanoresonators.<sup>184</sup> In this study, the authors validated a new dielectric sensing platform based on silicon nanodisks with strong optically induced MD resonances, which yielded a detection limit of streptavidin at the level of 5 ng mL<sup>-1</sup>. Yavas et al.<sup>185</sup> improved sensitivity of dielectric nanostructures by integrating arrays of antibody-functionalized silicon nanoresonators with microfluidics and demonstrated the detection of ~1 ng mL<sup>-1</sup> prostate specific antigen (PSA) in buffer. The sensing performance of dielectric Si nanodisks (a metasurface) was compared with that of gold nanorod arrays in a review article.<sup>186</sup> The authors showed that the dielectric metasurface possesses a better LOD compared to the plasmonic counterpart while the plasmonic nanorod metasurfaces afford a wider dynamic range.

Aoni et al.<sup>187</sup> proposed a dielectric metagrating platform for label-free optical biosensing based on an array of dielectric nanodiscs of different sizes, exhibiting individual Mie resonances. The nanodiscs were arranged in such a way that they could condition phase values from 0 to 2π in light transmitted through the structure (Fig. 14c). The whole structure presented a set of periodically repeated unit cells (highlighted by a dashed red line) to form a metagrating. The illumination of this structure by white light leads to the appearance of different diffraction orders in transmission and the intensity in these orders is conditioned by the phase ramp imprinted by the metagrating. It is critically important that under such a geometry the diffraction intensity ratio DIR = *I*<sub>-1</sub>/*I*<sub>0</sub> (where *I*<sub>-1</sub> and *I*<sub>0</sub> are intensities in high and zero orders, respectively) becomes highly sensitive to RI of the medium contacting the structure (Fig. 14c, right panel), which opens up access to the employment of such megagratings to control biological binding events. Depending on metagrating parameter, the structure can provide large or small deflection angles. The authors showed that smaller deflection angle (SDA) metagratings can provide better sensitive response to RI variations. An example of such SDA grating and corresponding transition spectra from different diffraction orders are shown in Fig. 14d and e. Fig. 14f (upper inset) displays the immobilisation of a primary antibody (Mouse IgG) onto a dielectric metagrating using silicon to amine/sulfhydryl coupling strategy. Testing of the sensitivity was performed with the help of an anti-Mouse IgG binding assay by measuring the diffraction intensity ratio of the 0th and -1st diffraction orders at a range of analyte concentrations from 5 × 10<sup>-10</sup> to 5 × 10<sup>-2</sup> mg mL<sup>-1</sup>, Fig. 14f. The resulting LOD of 0.1 ng mL<sup>-1</sup> for anti-Mouse IgG was achieved.<sup>187</sup>

We briefly mention that in addition to reflection/transmis-
sion/diffraction techniques, the fluorescence (FL) detection can
be used in combination with dielectric metasurfaces.<sup>188,189</sup>
Iwanaga et al.<sup>188</sup> suggested to employ dielectric metasurface
FL sensors for the detection of COVID-19 spike protein. The
enhanced intensity of FL allowed one to measure the glyco-
proteins and antibodies more efficiently, as compared to other

methods previously reported. The FL sensors based on a di-
electric metasurface demonstrated LOD less than 0.64 pg mL⁻¹
for glycoprotein peptides detection and the dynamic range was
more than five orders of the target concentrations.¹⁸⁸ The
highest-sensitivity biosensing FL platform was demonstrated
in ref. 189, where immunoglobulin G with concentrations of
the order of pg mL⁻¹ was detected.

Some efforts on developing the dielectric platform for biosensing were discussed in a recent review.¹⁹⁰ It is worth stressing that, despite being impressive, LODs achieved with dielectric metasurfaces and other dielectric platforms (~1 ng mL⁻¹) are well below LODs that one can achieve with plasmonic phase metamaterials (~1 fg mL⁻¹), see Fig. 2. This means that the dielectric platform could probably be further improved by employing phase as the sensing parameter at the condition of light darkness.

## 8.2 The concept of bound states in the continuum for highly sensitive biosensors

High-index all-dielectric metasurfaces have a disadvantage of a broad spectral response at ED and MD resonances severely restricting their LOD. It was recently found that sharp resonances could be achieved by utilising the concept of bound states in the continuum (BICs). Narrow resonances in BICs happen when light waves remain completely localized at a metasurface even though they coexist with a continuous electromagnetic spectrum of the environment.<sup>192,193</sup> While original BICs suggested by von Neumann and Wigner<sup>194</sup> are difficult to implement, there are other practical scenarios leading to the generation of BICs. For example, BICs can be realised in Fabry-Perot structures, coupled resonances (Friedrich-Wintgen (FW) BICs), parametric structures, etc.<sup>192</sup> Usually, BICs possess very high (theoretically divergent, but finite) values of the quality factor (Q) due to structural losses and imperfections.

An application of quasi-BIC resonances for biosensing was demonstrated in metasurfaces based on a dimer-type unit cell.<sup>195</sup> The authors performed real-time in-flow detection of biological extracellular vesicles (EVs) secreted from cancer cells with the help of an immunoassay. A quasi-BIC metasurface was integrated with a microfluidic flow channel resulting in the overall LOD of 126 ng mL<sup>-1</sup>.<sup>195</sup> Wu et al.<sup>196</sup> implemented a BIC-based biosensor using a compound grating waveguide structure with a switchable guided resonance. Due to a high Q-factor of ~7000, such a sensor provided LOD of the sucrose concentration at the level of 1.6 × 10<sup>-5</sup> g mL<sup>-1</sup>. An optical biosensor with a high quality factor, Q was engineered using the Friedrich-Wintgen type BICs.<sup>197</sup> This sensor is valuable in quality control analysis of food processing, for example for trace detection of a specific benchmark analyte, ochratoxyn A. Experimentally, a relatively low LOD of 2.3 pg mL<sup>-1</sup> was achieved. In addition, a FW-BIC type biosensor could be applied for the detection of other mycotoxins and low-molecular weight molecules. The topological light confinement effect in a quasi-BIC resonator was employed for PNA/DNA selective biosensing with real-time monitoring of binding events.<sup>198</sup> Measurements of transmittance spectra before and after the incubation with c-DNA (c = 0.05 nM)
<figure><img src="image_40.png" /></figure>

<figure><img src="image_41.png" /><figcaption>Fig. 15 Biosensor based on hetero-out-of-plane symmetry protected bound states in the continuum (BIC) metasurfaces. (a) Examples of metasurfaces with Sole In-plane (Δd) and Sole Out-of-plane (Δh) broken symmetry; (b) evolution of the position of q-BIC resonance generated in the hetero-out-of-plane (H-OP) geometry under the adsorption of endotoxin with concentration of 1 pg mL⁻¹ in a buffer solution; (c) dependence of q-BIC resonance position on endotoxin concentration. Adapted from ref. 191 with permission from John Wiley and Sons, copyright 2023.</figcaption></figure>

demonstrated the sensitivity of 20 molecules per µm². The authors expected further improvements toward the achievement of single molecule detection. Wang et al.¹⁹¹ suggested out-of-plane architectures based on symmetry protected (SP)-BIC metasurfaces as a high sensitive biosensor. They showed that hetero-out-of-plane (H-OP, Au-SiO₂, Fig. 15a) SP-BIC metasurfaces can exhibit a robust high Q-factor resonance suitable for biosensing. Fig. 15b shows a quasi-BIC (q-BIC) resonance shift of the H-OP architecture after the adsorption of endotoxin at the concentration of 1 pg mL⁻¹ in a PBS buffer solution. The experimental q-BIC resonance red-shifts with an increase of endotoxin concentration, as shown in Fig. 15c.

Kuhner et al.¹⁹⁹ designed symmetry-broken q-BICs ring structures based on a 120 nm thick amorphous silicon layer fabricated on a glass substrate using electron beam lithography and reactive ion etching. These structures demonstrated high-Q factors exceeding 500 in the red part of the visible spectrum. The bio-molecular sensing performance for asymmetric q-BICs structures was tested by the functionalisation with (3-amino-propyl) triethoxysilane (APTES), followed by the attachment of biotin molecules and binding of different concentrations of streptavidin protein. It was found that the proposed BIC platform provides polarization-invariant and tunable high-Q resonances in an ultra-compact footprint as low as 2 µm² resulting in LOD of 10 nM for streptavidin molecules.¹⁹⁹

Yesilkoy et al.²⁰⁰ used dielectric metasurfaces with q-BIC properties and combined them with hyperspectral imaging to develop an ultrasensitive label-free analytical platform for biosensing. In the proposed arrangement, a metasurface array was illuminated by a narrow-band tunable laser source, while transmitted light at each wavelength was recorded using a CMOS camera to examine spatially-resolved information at every pixel (Fig. 16a). Such a setup was used in combination with a metasurface architecture based on elliptical Si pairs of nanobars tilted around one of their axes (Fig. 16b). This design makes possible the excitation of BIC and q-BIC modes of collective lattice resonances at zero and non-zero (17.5°) tilting angles, respectively, while the spectral position of these

resonances can be tuned by changing resonator dimensions. The authors focused their attention on q-BIC modes, which were characterized by a strong localization of both electric and magnetic fields in the outer volume of Si pairs (Fig. 16c), making them especially useful for sensing applications. The authors also assessed biosensing performance of designed q-BICs in dielectric metasurface sensors in the geometry of image-based data processing. Rabbit-derived antimouse IgG was used as a test bio-object, while an epoxysilane chemistry was used to immobilize the receptor molecules (mouse-derived IgG) onto the sensor surface (Fig. 16d). As follows from Fig. 16e and f, a low areal molecule density of less than 1 × 10³ molecules per µm² could be detected using BIC metasurfaces with ultrasensitive hyperspectral imaging.²⁰⁰ Combined with a simplicity of information readout (expensive spectrometer equipment is not needed), such technique looks very promising for ultrasensitive spatially-resolved biosensing.

Finally, we note that despite a great progress in theory and application of BICs in biosensing, the achieved LODs are still on a moderate side which is not unexpected taken into account the infancy of this approach. Again, this approach could benefit significantly from the phase interrogation.

## 8.3 Exceptional point platform for biosensing

Another recent advance in optical label-free biosensing is related to the phenomenon of exceptional points (EP), which appear as spectral singularities in an open system described by a non-Hermitian Hamiltonian.²⁰¹⁻²⁰³ EPs can appear when at least two resonant modes coalesce to become degenerate both in their resonance frequencies and loss rates. Photonic systems look very promising for the implementation of EPs, which is confirmed by the observation of this phenomenon in many optical geometries.²⁰² Unique spectral properties of systems with EPs were theoretically suggested for single-particle detection via the monitoring of frequency and linewidth splitting of resonant modes.²⁰³ J. Wiersig et al.²⁰³ used a typical non-Hermitian optical system, in which EPs could be easily
<figure><img src="image_39.png" /></figure>

<figure><img src="image_40.png" /><figcaption>Fig. 15 Biosensor based on hetero-out-of-plane symmetry protected bound states in the continuum (BIC) metasurfaces. (a) Examples of metasurfaces with Sole In-plane (Δd) and Sole Out-of-plane (Δh) broken symmetry; (b) evolution of the position of q-BIC resonance generated in the hetero-out-of-plane (H-OP) geometry under the adsorption of endotoxin with concentration of 1 pg mL⁻¹ in a buffer solution; (c) dependence of q-BIC resonance position on endotoxin concentration. Adapted from ref. 191 with permission from John Wiley and Sons, copyright 2023.</figcaption></figure>

demonstrated the sensitivity of 20 molecules per µm². The authors expected further improvements toward the achievement of single molecule detection. Wang et al.¹⁹¹ suggested out-of-plane architectures based on symmetry protected (SP)-BIC metasurfaces as a high sensitive biosensor. They showed that hetero-out-of-plane (H-OP, Au-SiO₂, Fig. 15a) SP-BIC metasurfaces can exhibit a robust high Q-factor resonance suitable for biosensing. Fig. 15b shows a quasi-BIC (q-BIC) resonance shift of the H-OP architecture after the adsorption of endotoxin at the concentration of 1 pg mL⁻¹ in a PBS buffer solution. The experimental q-BIC resonance red-shifts with an increase of endotoxin concentration, as shown in Fig. 15c.

Kuhner et al.¹⁹⁹ designed symmetry-broken q-BICs ring structures based on a 120 nm thick amorphous silicon layer fabricated on a glass substrate using electron beam lithography and reactive ion etching. These structures demonstrated high-Q factors exceeding 500 in the red part of the visible spectrum. The bio-molecular sensing performance for asymmetric q-BICs structures was tested by the functionalisation with (3-amino-propyl) triethoxysilane (APTES), followed by the attachment of biotin molecules and binding of different concentrations of streptavidin protein. It was found that the proposed BIC platform provides polarization-invariant and tunable high-Q resonances in an ultra-compact footprint as low as 2 µm² resulting in LOD of 10 nM for streptavidin molecules.¹⁹⁹

Yesilkoy et al.²⁰⁰ used dielectric metasurfaces with q-BIC properties and combined them with hyperspectral imaging to develop an ultrasensitive label-free analytical platform for biosensing. In the proposed arrangement, a metasurface array was illuminated by a narrow-band tunable laser source, while transmitted light at each wavelength was recorded using a CMOS camera to examine spatially-resolved information at every pixel (Fig. 16a). Such a setup was used in combination with a metasurface architecture based on elliptical Si pairs of nanobars tilted around one of their axes (Fig. 16b). This design makes possible the excitation of BIC and q-BIC modes of collective lattice resonances at zero and non-zero (17.5°) tilting angles, respectively, while the spectral position of these

resonances can be tuned by changing resonator dimensions. The authors focused their attention on q-BIC modes, which were characterized by a strong localization of both electric and magnetic fields in the outer volume of Si pairs (Fig. 16c), making them especially useful for sensing applications. The authors also assessed biosensing performance of designed q-BICs in dielectric metasurface sensors in the geometry of image-based data processing. Rabbit-derived antimouse IgG was used as a test bio-object, while an epoxysilane chemistry was used to immobilize the receptor molecules (mouse-derived IgG) onto the sensor surface (Fig. 16d). As follows from Fig. 16e and f, a low areal molecule density of less than 1 × 10³ molecules per µm² could be detected using BIC metasurfaces with ultrasensitive hyperspectral imaging.²⁰⁰ Combined with a simplicity of information readout (expensive spectrometer equipment is not needed), such technique looks very promising for ultrasensitive spatially-resolved biosensing.

Finally, we note that despite a great progress in theory and application of BICs in biosensing, the achieved LODs are still on a moderate side which is not unexpected taken into account the infancy of this approach. Again, this approach could benefit significantly from the phase interrogation.

## 8.3 Exceptional point platform for biosensing

Another recent advance in optical label-free biosensing is related to the phenomenon of exceptional points (EP), which appear as spectral singularities in an open system described by a non-Hermitian Hamiltonian.²⁰¹⁻²⁰³ EPs can appear when at least two resonant modes coalesce to become degenerate both in their resonance frequencies and loss rates. Photonic systems look very promising for the implementation of EPs, which is confirmed by the observation of this phenomenon in many optical geometries.²⁰² Unique spectral properties of systems with EPs were theoretically suggested for single-particle detection via the monitoring of frequency and linewidth splitting of resonant modes.²⁰³ J. Wiersig et al.²⁰³ used a typical non-Hermitian optical system, in which EPs could be easily
<figure><img src="image_42.png" /><figcaption>**Fig. 16** Dielectric metasurfaces with q-BIC properties combined with hyperspectral imaging for highly-sensitive spatially-resolved biosensing. (a) Schematic of hyperspectral imaging scheme. An all-dielectric metasurface array is illuminated at a tuneable wavelength. A CMOS camera is then used to create a hyperspectral data cube, in which every pixel records spectral information in transmitted light; (b) SEM images of used all-dielectric metasurface composed of pairs of Si nanobars; (c) distribution of electric and magnetic fields in a pair of Si nanobars in the case of BIC and q-BIC modes. (d)–(f) Biosensing testing of metasurfaces enabling q-PIC modes in the detection of rabbit-derived antimouse immunoglobulin IgG (R-IgG). (d) Schematic of bioassay. The sensor surface is functionalized with mouse-derived IgG (M-IgG), which has a high affinity to R-IgG; (e) mean resonance shift as a function of number of R-IgG molecules. The dependence is presented in the form of a traditional calibration curve correlating the ensemble-averaged resonance shift from binding spots to the average number of R-IgG molecules per µm². Colour bars indicate data points associated to the resonance shift maps; (f) area under the curve (AUC) values of all receiver operating characteristic (ROC) curves. Control measurements revealed an AUC value of 0.5008 ± 0.0291 (N = 68), which gave evidence for the detection level at very low molecular counts (~3 molecules per µm²). Adapted from ref. 200 with permission from Springer Nature, copyright 2019.</figcaption></figure>

interpreted. The authors studied two coupled whispering gallery microcavity (WGM) waveguides, whose resonant frequencies, losses and gains were carefully selected to generate EPs. As WGMs utilize total internal reflection to localize light in the cavity, the resulting resonances at EPs exhibited a very high Q-factor, which is important for high-sensitive particle detection.²⁰²,²⁰³ An improvement of sensing performance in the geometry of optical microcavity was reported in ref. 204. Here, a target molecule entering the evanescent field of the microcavity near EPs perturbed the system, leading to a frequency

splitting, which could be large enough to detect a single molecule. Further improvements of optical biosensing performance can be achieved via the employment of a coupled system consisting of graphene plasmons (implemented in patterned graphene ribbons) and molecule vibrational modes, in which the coupling strength can be tuned from “strong” to “weak” coupling regimes yielding EPs of non-Hermitian origin.²⁰⁵ The authors theoretically showed that the sensitivity of this hybrid plasmon/vibrational system to RI variations can be maximized by selecting the thicknesses of plasmonic film and the numbers

<figure><img src="image_43.png" /></figure>
<figure><img src="image_41.png" /></figure>

<figure><img src="image_42.png" /><figcaption>**Fig. 16** Dielectric metasurfaces with q-BIC properties combined with hyperspectral imaging for highly-sensitive spatially-resolved biosensing. (a) Schematic of hyperspectral imaging scheme. An all-dielectric metasurface array is illuminated at a tuneable wavelength. A CMOS camera is then used to create a hyperspectral data cube, in which every pixel records spectral information in transmitted light; (b) SEM images of used all-dielectric metasurface composed of pairs of Si nanobars; (c) distribution of electric and magnetic fields in a pair of Si nanobars in the case of BIC and q-BIC modes. (d)–(f) Biosensing testing of metasurfaces enabling q-PIC modes in the detection of rabbit-derived antimouse immunoglobulin IgG (R-IgG). (d) Schematic of bioassay. The sensor surface is functionalized with mouse-derived IgG (M-IgG), which has a high affinity to R-IgG; (e) mean resonance shift as a function of number of R-IgG molecules. The dependence is presented in the form of a traditional calibration curve correlating the ensemble-averaged resonance shift from binding spots to the average number of R-IgG molecules per µm². Colour bars indicate data points associated to the resonance shift maps; (e) area under the curve (AUC) values of all receiver operating characteristic (ROC) curves. Control measurements revealed an AUC value of 0.5008 ± 0.0291 (N = 68), which gave evidence for the detection level at very low molecular counts (~3 molecules per µm²). Adapted from ref. 200 with permission from Springer Nature, copyright 2019.</figcaption></figure>

interpreted. The authors studied two coupled whispering gallery microcavity (WGM) waveguides, whose resonant frequencies, losses and gains were carefully selected to generate EPs. As WGMs utilize total internal reflection to localize light in the cavity, the resulting resonances at EPs exhibited a very high Q-factor, which is important for high-sensitive particle detection.²⁰²,²⁰³ An improvement of sensing performance in the geometry of optical microcavity was reported in ref. 204. Here, a target molecule entering the evanescent field of the microcavity near EPs perturbed the system, leading to a frequency

splitting, which could be large enough to detect a single molecule. Further improvements of optical biosensing performance can be achieved via the employment of a coupled system consisting of graphene plasmons (implemented in patterned graphene ribbons) and molecule vibrational modes, in which the coupling strength can be tuned from “strong” to “weak” coupling regimes yielding EPs of non-Hermitian origin.²⁰⁵ The authors theoretically showed that the sensitivity of this hybrid plasmon/vibrational system to RI variations can be maximized by selecting the thicknesses of plasmonic film and the numbers
Review Article

<figure><img src="image_44.png" /></figure>

of graphene layers in the ribbons to tune the system to the generation of efficient EPs. Bin Liu et al.²⁰⁶ proposed a biosensing design based on a microtube cavity having multiple layers, in which the coupling of modes can be tailored to generate EPs by a careful selection of layer thicknesses. It was theoretically shown that the proposed biosensor design could provide the improvement of sensitivity up to 1000-fold compared to conventional methods. A label-free optical biosensor based on optical tunnelling was theoretically suggested in ref. 207. The calculated LOD for the system was found to be 0.9 ng mL⁻¹. The authors envisaged the application of this biosensor based on EP metamaterial modes in environment protection, drinking water safety, and drug screening.

Park et al.²⁰⁸ reported the observation of EPs in plasmonic systems, which looks especially promising for the implementation of biosensing devices. The authors used a bilayer periodic plasmonic structure (metallo-dielectric photonic crystal) made

of two optically dissimilar plasmonic resonators (Fig. 17). The detuning of resonances in such a system was achieved via an out-of-plane symmetry breaking using identical resonators in distinct optical environments, as shown in Fig. 17a and b (alternatively, the detuning can be done using plasmonic nanostructures of different size in a uniform optical environment). The authors showed that in the case of optically identical resonators the generation of EPs is impossible and hybridized resonances cross along a diabolic line (at so-called diabolic points, DP) as a function of $d_x$ and $P_y$. In contrast, in the case of optically dissimilar resonators one can obtain hybrid modes with crossing and avoided crossing of both the resonances and loss rates, which yields the generation of plasmonic EP where resonances and loss rates become simultaneously degenerate (Fig. 17c). It was also concluded from calculations and experiments that the biosensor operating around an EP and DP exhibits a resonance splitting ($\Delta\omega$)

<figure><img src="image_45.png" /><figcaption>(b)</figcaption></figure>

<figure><img src="image_46.png" /><figcaption>(d)</figcaption></figure>

<figure><img src="image_47.png" /><figcaption>(c)</figcaption></figure>

<figure><img src="image_48.png" /><figcaption>(e)</figcaption></figure>

<figure><img src="image_49.png" /></figure>

**Fig. 17** Implementation of EPs in multi-layered plasmon system and their biosensing assessment. (a) Schematic of a bilayer metallo-dielectric photonic crystal made of two optically dissimilar plasmonic resonators. The resonances are detuned via the employment of identical plasmonic resonators based on gold metallic bars (length 250 nm, width 50 nm, thickness 40 nm) placed in two different optical environments (air and polymer SU-8); (b) Top (upper) and side (lower) views of the used metallo-dielectric photonic crystal. The period along the x direction is fixed to $P_x$ = 400 nm while $P_y$ and $d_x$ are the two parameters used to reach an EP; (c) real and imaginary parts of the eigenmodes (red and blue) of hybridized plasmonic resonators arrays of identical size (in different environments), shown in panel (b), as a function of $P_y$ and $d_x$. At some point corresponding to the generation of EP (green dot), the hybridization of optically dissimilar resonators provides two hybrid modes with crossing and avoided crossing of both the resonances and loss rates, and resonances and loss rates become simultaneously degenerate. (d) and (e) Immuno-assay biosensing using plasmonic EPs and diabolic points (DPs). (b) Dependence of resonance splitting $\Delta\omega$ in EP and DP sensors on anti-mouse IgG concentration. The inset demonstrated a functionalization strategy using a linker and a mouse IgG as a receptor. One can see that the EP are more sensitive than DPs under small anti-IgG concentrations. (e) Dependence of resonance splitting $\Delta\omega$ on the perturbation $\epsilon$ = (anti-IgG concentration aM)/(1100 aM) for the EP and DP sensors. One can see a square-root and linear dependence of resonance splitting on IgG concentration for the EP and DP sensors, respectively. Adapted from ref. 208 with permission from Springer Nature, copyright 2020.
Review Article

of graphene layers in the ribbons to tune the system to the generation of efficient EPs. Bin Liu et al.²⁰⁶ proposed a biosensing design based on a microtube cavity having multiple layers, in which the coupling of modes can be tailored to generate EPs by a careful selection of layer thicknesses. It was theoretically shown that the proposed biosensor design could provide the improvement of sensitivity up to 1000-fold compared to conventional methods. A label-free optical biosensor based on optical tunnelling was theoretically suggested in ref. 207. The calculated LOD for the system was found to be 0.9 ng mL⁻¹. The authors envisaged the application of this biosensor based on EP metamaterial modes in environment protection, drinking water safety, and drug screening.

Park et al.²⁰⁸ reported the observation of EPs in plasmonic systems, which looks especially promising for the implementation of biosensing devices. The authors used a bilayer periodic plasmonic structure (metallo-dielectric photonic crystal) made

of two optically dissimilar plasmonic resonators (Fig. 17). The detuning of resonances in such a system was achieved via an out-of-plane symmetry breaking using identical resonators in distinct optical environments, as shown in Fig. 17a and b (alternatively, the detuning can be done using plasmonic nanostructures of different size in a uniform optical environment). The authors showed that in the case of optically identical resonators the generation of EPs is impossible and hybridized resonances cross along a diabolic line (at so-called diabolic points, DP) as a function of $d_x$ and $P_y$. In contrast, in the case of optically dissimilar resonators one can obtain hybrid modes with crossing and avoided crossing of both the resonances and loss rates, which yields the generation of plasmonic EP where resonances and loss rates become simultaneously degenerate (Fig. 17c). It was also concluded from calculations and experiments that the biosensor operating around an EP and DP exhibits a resonance splitting ($\Delta\omega$)

<figure><img src="image_43.png" /></figure>

<figure><img src="image_44.png" /><figcaption>**Fig. 17** Implementation of EPs in multi-layered plasmon system and their biosensing assessment. (a) Schematic of a bilayer metallo-dielectric photonic crystal made of two optically dissimilar plasmonic resonators. The resonances are detuned via the employment of identical plasmonic resonators based on gold metallic bars (length 250 nm, width 50 nm, thickness 40 nm) placed in two different optical environments (air and polymer SU-8); (b) Top (upper) and side (lower) views of the used metallo-dielectric photonic crystal. The period along the x direction is fixed to $P_x$ = 400 nm while $P_y$ and $d_x$ are the two parameters used to reach an EP; (c) real and imaginary parts of the eigenmodes (red and blue) of hybridized plasmonic resonators arrays of identical size (in different environments), shown in panel (b), as a function of $P_y$ and $d_x$. At some point corresponding to the generation of EP (green dot), the hybridization of optically dissimilar resonators provides two hybrid modes with crossing and avoided crossing of both the resonances and loss rates, and resonances and loss rates become simultaneously degenerate. (d) and (e) Immuno-assay biosensing using plasmonic EPs and diabolic points (DPs). (b) Dependence of resonance splitting $\Delta\omega$ in EP and DP sensors on anti-mouse IgG concentration. The inset demonstrated a functionalization strategy using a linker and a mouse IgG as a receptor. One can see that the EP are more sensitive than DPs under small anti-IgG concentrations. (e) Dependence of resonance splitting $\Delta\omega$ on the perturbation $\epsilon$ = (anti-IgG concentration aM)/(1100 aM) for the EP and DP sensors. One can see a square-root and linear dependence of resonance splitting on IgG concentration for the EP and DP sensors, respectively. Adapted from ref. 208 with permission from Springer Nature, copyright 2020.</figcaption></figure>
proportional to the square root and linear value of the perturbation, respectively.²⁰⁸ The authors demonstrated that suggested nanoantenna arrays with EP enables enhanced sensing of anti-immunoglobulin G (IgG). Data in Fig. 17d and e show the sensitivity to low concentrations of anti-mouse IgG for two sensors based on plasmonic EP and DP modes. Here, designed plasmonic EP nanoantenna arrays demonstrated LOD of 15 fg mL⁻¹ which is better than many available plasmonic biosensor platforms.

## 8.4 Label-free optical detection of single molecules

Finally, we briefly discuss the problem of label-free optical detection of single molecules. The conciseness of discussion will be connected to the fact that: (i) excellent reviews on the subject already exist;²⁰⁹,²¹⁰ (ii) it is difficult to currently envisage how this technology could be widely employed in biomedical diagnostics, environment and food safety, security and health applications. Single molecule detection (SMD) could serve for many important tasks, including the control of molecular (digital) binding kinetics, monitoring of dynamics and constants of cells, quantification of exosomes, and the investigation of motor protein functions, detection of drugs, etc. SMD is typically based on microscopy modalities, which limits its usage to laboratory environment. However, SMD provides an ultimate sensitivity level in biosensing and hence deserves a brief overview.

One of the most promising microscopies for SMD is based on SPR imaging technology.²³ SPR imaging was recently significantly upgraded by the emergence of plasmonic scattering microscopy, which was then successfully applied for the detection of different analytes yielding LODs at a single-protein level.²¹¹ While traditional SPR imaging systems measure the intensity of reflected light, plasmonic scattering microscopy deals with out-of-plane scattered surface plasmonic waves produced as the result of the interaction of plasmonic system with analytes. The authors claimed that their method allows one to achieve a SPR imaging option with high spatiotemporal resolution, as well obtain information on binding kinetics. A recent review²⁰⁹ was focused on emerging applications of plasmonic scattering microscopy for single-protein imaging and single-cell analysis. As one of examples, nanofluidic scattering microscopy was applied for SMD in ref. 212.

Another important method for SMD is based on interferometric scattering microscopy (iSCAT), which is an extremely sensitive technique due to the combination of two factors: the ability to detect weak signals and the ability to separate these signals from a background.²¹⁰ Interferometric scattering microscopy can be used for high-speed single particle tracking, quantitative single-molecule characterization, and measurements of bio-molecular kinetics. It was shown that with the help of iSCAT one can obtain a high signal-to-noise ratio visualization of assemblies of biological materials such as proteins and lipids without the need for labels. It was also recently shown that iSCAT could become a promising tool for elucidating bio-molecular mechanisms on the plasma membrane.²¹³,²¹⁴

At the end of this section, we note that while applications of the microscopy methods for SMD requires a high-tech equipment, one could imagine their broader usage in a near future as microscopy can be implemented in extremely small volumes (as Leeuwenhoek showed in XVII century).

# 9. Current challenges and future perspectives of label-free ultra-sensitive plasmonic biosensors

Newly-emerging optical biosensors based on new structural architectures and new materials, including emerging metamaterials, hybrid plasmonic-2D metasurfaces, metal/dielectric nanostructures, all-dielectric metasurfaces, are capable of generating a variety of novel phenomena, which can be employed to radically upgrade the sensitivity of current label-free biosensing technology and offer new attractive functionalities (imaging and multi-sensing option, superresolution, spectral tuneability, size selectivity, new functionalization strategies, etc.). In particular, designed plasmonic metamaterials open access to unprecedented ag mm⁻² levels of areal mass sensitivity³³ and in some cases the reported LOD values were 3 orders of magnitude lower compared to all existing label-free and label-based biosensing methods.³⁸ The use of metamaterial-based architectures in combination with phase interrogation looks especially promising as it can lead to much lower limits of detection for a variety of small molecular weight analytes, see Fig. 2. At the same time, a great progress was achieved in dielectric biosensing platforms and platforms based on bound states in continuum and exceptional points. Extremely low LOD was reported for the biosensors based on the Goos-Hänchen effect and hyperbolic metamaterials.

Despite their extremely appealing characteristics, newly-emerging optical label-free technologies still require further instrumental elaboration and adaptation for concrete tasks of biomedical research. Current challenges and opportunities include the following:

1. The discussed label-free optical biosensing methods and metamaterial-based architectures can indeed provide an unprecedented improvement in the sensitivity of optical label-free biosensing, reaching the level of label methods (or better). However, high sensitivity often comes at the price of a limited dynamic range. Fortunately, as shown in ref. 38, even in the case of a very narrow dynamic range (e.g., conditioned by a limited phase jump in phase-sensitive interrogation), a binding event can be accurately resolved by applying appropriate averaging and filtering algorithms. The limited dynamic range problem can be also tackled by employing feedback loops to keep the system within the range of maximal phase variation and/or by using additional signal recording channels.

2. An obstacle for the wide application of metamaterial-based sensor technology is related to the relative complexity of optical measurement instrumentation. For en masse applications, sensors should be based on inexpensive, robust and ready-to-use optical designs. We believe that some of the

<figure><img src="image_50.png" /></figure>
proportional to the square root and linear value of the perturbation, respectively.²⁰⁸ The authors demonstrated that suggested nanoantenna arrays with EP enables enhanced sensing of anti-immunoglobulin G (IgG). Data in Fig. 17d and e show the sensitivity to low concentrations of anti-mouse IgG for two sensors based on plasmonic EP and DP modes. Here, designed plasmonic EP nanoantenna arrays demonstrated LOD of 15 fg mL⁻¹ which is better than many available plasmonic biosensor platforms.

## 8.4 Label-free optical detection of single molecules

Finally, we briefly discuss the problem of label-free optical detection of single molecules. The conciseness of discussion will be connected to the fact that: (i) excellent reviews on the subject already exist;²⁰⁹,²¹⁰ (ii) it is difficult to currently envisage how this technology could be widely employed in biomedical diagnostics, environment and food safety, security and health applications. Single molecule detection (SMD) could serve for many important tasks, including the control of molecular (digital) binding kinetics, monitoring of dynamics and constants of cells, quantification of exosomes, and the investigation of motor protein functions, detection of drugs, etc. SMD is typically based on microscopy modalities, which limits its usage to laboratory environment. However, SMD provides an ultimate sensitivity level in biosensing and hence deserves a brief overview.

One of the most promising microscopies for SMD is based on SPR imaging technology.²³ SPR imaging was recently significantly upgraded by the emergence of plasmonic scattering microscopy, which was then successfully applied for the detection of different analytes yielding LODs at a single-protein level.²¹¹ While traditional SPR imaging systems measure the intensity of reflected light, plasmonic scattering microscopy deals with out-of-plane scattered surface plasmonic waves produced as the result of the interaction of plasmonic system with analytes. The authors claimed that their method allows one to achieve a SPR imaging option with high spatiotemporal resolution, as well obtain information on binding kinetics. A recent review²⁰⁹ was focused on emerging applications of plasmonic scattering microscopy for single-protein imaging and single-cell analysis. As one of examples, nanofluidic scattering microscopy was applied for SMD in ref. 212.

Another important method for SMD is based on interferometric scattering microscopy (iSCAT), which is an extremely sensitive technique due to the combination of two factors: the ability to detect weak signals and the ability to separate these signals from a background.²¹⁰ Interferometric scattering microscopy can be used for high-speed single particle tracking, quantitative single-molecule characterization, and measurements of bio-molecular kinetics. It was shown that with the help of iSCAT one can obtain a high signal-to-noise ratio visualization of assemblies of biological materials such as proteins and lipids without the need for labels. It was also recently shown that iSCAT could become a promising tool for elucidating bio-molecular mechanisms on the plasma membrane.²¹³,²¹⁴

At the end of this section, we note that while applications of the microscopy methods for SMD requires a high-tech equipment, one could imagine their broader usage in a near future as microscopy can be implemented in extremely small volumes (as Leeuwenhoek showed in XVII century).

# 9. Current challenges and future perspectives of label-free ultra-sensitive plasmonic biosensors

Newly-emerging optical biosensors based on new structural architectures and new materials, including emerging metamaterials, hybrid plasmonic-2D metasurfaces, metal/dielectric nanostructures, all-dielectric metasurfaces, are capable of generating a variety of novel phenomena, which can be employed to radically upgrade the sensitivity of current label-free biosensing technology and offer new attractive functionalities (imaging and multi-sensing option, superresolution, spectral tuneability, size selectivity, new functionalization strategies, etc.). In particular, designed plasmonic metamaterials open access to unprecedented ag mm⁻² levels of areal mass sensitivity³³ and in some cases the reported LOD values were 3 orders of magnitude lower compared to all existing label-free and label-based biosensing methods.³⁸ The use of metamaterial-based architectures in combination with phase interrogation looks especially promising as it can lead to much lower limits of detection for a variety of small molecular weight analytes, see Fig. 2. At the same time, a great progress was achieved in dielectric biosensing platforms and platforms based on bound states in continuum and exceptional points. Extremely low LOD was reported for the biosensors based on the Goos-Hänchen effect and hyperbolic metamaterials.

Despite their extremely appealing characteristics, newly-emerging optical label-free technologies still require further instrumental elaboration and adaptation for concrete tasks of biomedical research. Current challenges and opportunities include the following:

1. The discussed label-free optical biosensing methods and metamaterial-based architectures can indeed provide an unprecedented improvement in the sensitivity of optical label-free biosensing, reaching the level of label methods (or better). However, high sensitivity often comes at the price of a limited dynamic range. Fortunately, as shown in ref. 38, even in the case of a very narrow dynamic range (e.g., conditioned by a limited phase jump in phase-sensitive interrogation), a binding event can be accurately resolved by applying appropriate averaging and filtering algorithms. The limited dynamic range problem can be also tackled by employing feedback loops to keep the system within the range of maximal phase variation and/or by using additional signal recording channels.

2. An obstacle for the wide application of metamaterial-based sensor technology is related to the relative complexity of optical measurement instrumentation. For *en masse* applications, sensors should be based on inexpensive, robust and ready-to-use optical designs. We believe that some of the

<figure><img src="image_45.png" /></figure>
Review Article

discussed designs can indeed be compact and mobile, and can
be used at the point-of-action or even at homes. As examples,
one can imagine the development of miniaturized designs
based on planar and fiber waveguide couplers,¹⁰³,¹⁰⁶,¹⁰⁷ compact
integrated SPR interferometers¹⁰⁴ and Si-based integrating
optics.¹⁰⁸,¹⁰⁹ In future, new biosensor layouts could be incor-
porated in mobile phones,¹¹⁰ which have the architecture
necessary to perform optical biosensing provided the functio-
nalized biosensing chips are available.

3. The development of low-cost and robust sensor transducers presents another important challenge. In this respect, Fourier nano-transducers and topologically dark metamaterials may have the edge from the point-of-view of simplicity and robustness, as they do not depend on local imperfections or structural non-uniformities. On the other hand, the low-cost fabrication of slides with the optical biochips is challenging. However, we believe that the problem could be solved by the development and adaptation of low-cost and scalable methods, including laser ablation (see an example in ref. 215), self-assembly or inkjet printing.

4. Functionalization is an essential part of any selective biosensing. Modern label-free optical sensors rely on bio-functionalization of gold. The surface of gold looks advantageous as the surface chemistry of gold is straightforward, while functionalization protocols are well developed for a variety of molecules used in biosensing. At the same time, 2D materials provide an excellent opportunity for bio-functionalization, especially in hybrid platforms, which combine 2D materials with conventional metal plasmonics. Recently, the protection of copper and silver plasmonics with 2D materials was demonstrated,³⁴ which led to the development of the layered material platform for biosensing.⁶⁰ In this platform, graphene-based surfaces allow the selective absorption of some molecules through pi-stacking forces, which opens up new avenues in bio-functionalization which is refreshingly different from gold bio-functionalization and allows the study of aromatic rings in bio-objects such as DNA, RNA, peptides, and cytokines.³⁵

5. Last but not least, 2D atomic materials possess natural plasmons and phonon-polaritons which can provide sharp resonances useful for biosensing.126,216 The main attraction of these resonances comes from the fact that they have frequencies overlapping with vibrational frequencies of biomolecules. Hence, in addition to detecting refractive index changes near nano-resonators, natural plasmons in 2D materials can also provide selectivity of detection without any use of functionalization through measuring subtle changes of resonant infrared spectra.126,216 This attractive feature could lead to new biosensing platforms and the possibilities of biosensing provided by flat optics are still to be explored.

To conclude, there exist methods and architectures that
provide unrivalled sensitivity of optical label-free biosensing
that go well beyond the limits of detection of standard SPR and
LPR platforms. We believe that future of label-free optical
biosensing lies with simple, yet ingenious metamaterials
(e.g., Fourier nano-transducers/diffractive nonlocal media)
which would guarantee quantitative point-of-care or point-of-
action biosensing from simple unobtrusive test.

Author contributions

A. V. K. and A. N. G. conceived this review article and planned its content. A. V. K., V. G. K. and A. N. G. carried out an extensive research and analysis of the literature related to the subject, and wrote different parts of the manuscript. A. V. K. and A. N. G. assembled all parts and formulated the main ideas of the manuscript. All authors worked on the revised version of the article. A. V. K. and A. N. G. guided the project.

Conflicts of interest

There are no conflicts to declare.

Acknowledgements

AVK acknowledges financial support of the CNRS-DRI Interna-
tional Research Project (IRP) “MINOS” ANG and VGK acknow-
ledge the support of Graphene Flagship Grant, Core 3 (881603).
The authors also thank Prof. Irina Grigorieva for her invaluable
help in preparing the manuscript.

References

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Review Article

discussed designs can indeed be compact and mobile, and can be used at the point-of-action or even at homes. As examples, one can imagine the development of miniaturized designs based on planar and fiber waveguide couplers,<sup>103,106,107</sup> compact integrated SPR interferometers<sup>104</sup> and Si-based integrating optics.<sup>108,109</sup> In future, new biosensor layouts could be incorporated in mobile phones,<sup>110</sup> which have the architecture necessary to perform optical biosensing provided the functionalized biosensing chips are available.

3. The development of low-cost and robust sensor transducers presents another important challenge. In this respect, Fourier nano-transducers and topologically dark metamaterials may have the edge from the point-of-view of simplicity and robustness, as they do not depend on local imperfections or structural non-uniformities. On the other hand, the low-cost fabrication of slides with the optical biochips is challenging. However, we believe that the problem could be solved by the development and adaptation of low-cost and scalable methods, including laser ablation (see an example in ref. 215), self-assembly or inkjet printing.

4. Functionalization is an essential part of any selective biosensing. Modern label-free optical sensors rely on bio-functionalization of gold. The surface of gold looks advantageous as the surface chemistry of gold is straightforward, while functionalization protocols are well developed for a variety of molecules used in biosensing. At the same time, 2D materials provide an excellent opportunity for bio-functionalization, especially in hybrid platforms, which combine 2D materials with conventional metal plasmonics. Recently, the protection of copper and silver plasmonics with 2D materials was demonstrated,<sup>34</sup> which led to the development of the layered material platform for biosensing.<sup>60</sup> In this platform, graphene-based surfaces allow the selective absorption of some molecules through pi-stacking forces, which opens up new avenues in bio-functionalization which is refreshingly different from gold bio-functionalization and allows the study of aromatic rings in bio-objects such as DNA, RNA, peptides, and cytokines.<sup>35</sup>

5. Last but not least, 2D atomic materials possess natural plasmons and phonon-polaritons which can provide sharp resonances useful for biosensing.<sup>126,216</sup> The main attraction of these resonances comes from the fact that they have frequencies overlapping with vibrational frequencies of biomolecules. Hence, in addition to detecting refractive index changes near nano-resonators, natural plasmons in 2D materials can also provide selectivity of detection without any use of functionalization through measuring subtle changes of resonant infrared spectra.<sup>126,216</sup> This attractive feature could lead to new biosensing platforms and the possibilities of biosensing provided by flat optics are still to be explored.

To conclude, there exist methods and architectures that provide unrivalled sensitivity of optical label-free biosensing that go well beyond the limits of detection of standard SPR and LPR platforms. We believe that future of label-free optical biosensing lies with simple, yet ingenious metamaterials (e.g., Fourier nano-transducers/diffractive nonlocal media) which would guarantee quantitative point-of-care or point-of-action biosensing from simple unobtrusive test.

Author contributions

A. V. K. and A. N. G. conceived this review article and planned its content. A. V. K., V. G. K. and A. N. G. carried out an extensive research and analysis of the literature related to the subject, and wrote different parts of the manuscript. A. V. K. and A. N. G. assembled all parts and formulated the main ideas of the manuscript. All authors worked on the revised version of the article. A. V. K. and A. N. G. guided the project.

Conflicts of interest

There are no conflicts to declare.

Acknowledgements

AVK acknowledges financial support of the CNRS-DRI International Research Project (IRP) "MINOS" ANG and VGK acknowledge the support of Graphene Flagship Grant, Core 3 (881603). The authors also thank Prof. Irina Grigorieva for her invaluable help in preparing the manuscript.

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<figure><img src="image_47.png" /></figure>
<figure><img src="image_52.png" /></figure>

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158 X. Yang, L. Xiong, Y. Lu and G. Li, *J. Phys. D: Appl. Phys.*, 2020, 53, 465109.

159 I. Barth, D. Conteduca, C. Reardon, S. Johnson and T. F. Krauss, *Light: Sci. Appl.*, 2020, **9**, 96.

160 A. Overvig and A. Alù, *Laser Photonics Rev.*, 2022, 2100633.

161 H. Song, N. Zhang, J. Duan, Z. Liu, J. Gao, M. H. Singer, D. Ji, A. R. Cheney, X. Zeng, B. Chen, S. Jiang and Q. Gan, *Adv. Opt. Mater.*, 2017, 5, 1700166.

162 C. Coutant, S. Ravaine, X. Wang, J. Toudert, V. Ponsinet and P. Barois, *Rendiconti Lincei*, 2015, **26**, 175–182.

163 A. I. Aristov, M. Manousidaki, A. Danilov, K. Terzaki, C. Fotakis, M. Farsari and A. V. Kabashin, *Sci. Rep.*, 2016, **6**, 1–8.

164 K. V. Sreekanth, S. Sreejith, S. Han, A. Mishra, X. Chen, H. Sun, C. T. Lim and R. Singh, *Nat. Commun.*, 2018, **9**, 369.
<figure><img src="image_53.png" /></figure>

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165 V. Sreekanth, M. ElKabbash, V. Caligiuri, R. Singh, A. De Luca and G. Strangi, *New Directions in Thin Film Nanophotonics*, Springer Singapore, 2019.

166 L. Jiang, S. Zeng, Z. Xu, Q. Ouyang, D. H. Zhang, P. H. J. Chong, P. Coquet, S. He and K. T. Yong, *Small*, 2017, **13**, 1700600.

167 Y. Zou, Y. Liu and G. Song, *Sensors*, 2022, **22**, 2116.

168 F. Goos and H. Hänchen, *Ann. Phys.*, 1947, **436**, 333–346.

169 F. Goos and H. Lindberg-Hänchen, *Ann. Phys.*, 1949, **440**, 251–252.

170 X. Yin, L. Hesselink, Z. Liu, N. Fang and X. Zhang, *Appl. Phys. Lett.*, 2004, **85**, 372–374.

171 R.-G. Wan and M. S. Zubairy, *Opt. Express*, 2020, **28**, 6036–6047.

172 Z. Qin, C. Yue, Y. Lang and Q. Liu, *Opt. Commun.*, 2018, **426**, 16–22.

173 Z. Liu, F. Lu, L. Jiang, W. Lin and Z. Zheng, *Biosensors*, 2021, **11**, 201.

174 S. Zeng, G. Liang, A. Gheno, S. Vedraine, B. Ratier, H.-P. Ho and N. Yu, *Nanomaterials*, 2020, **10**, 1289.

175 Q. You, Y. Shan, S. Gan, Y. Zhao, X. Dai and Y. Xiang, *Opt. Mater. Express*, 2018, **8**, 3036–3048.

176 L. Han, J. Pan, C. Wu, K. Li, H. Ding, Q. Ji, M. Yang, J. Wang, H. Zhang and T. Huang, *Sensors*, 2020, **20**, 1028.

177 K. V. Sreekanth, Q. Ouyang, S. Han, K.-T. Yong and R. Singh, *Appl. Phys. Lett.*, 2018, **112**, 161109.

178 C.-W. Chang, X. Xu, S. Chakravarty, H.-C. Huang, L.-W. Tu, Q. Y. Chen, H. Dalir, M. A. Krainak and R. T. Chen, *Biosens. Bioelectron.*, 2019, **141**, 111396.

179 K. V. Sreekanth, W. Dong, Q. Ouyang, S. Sreejith, M. ElKabbash, C. T. Lim, G. Strangi, K.-T. Yong, R. E. Simpson and R. Singh, *ACS Appl. Mater. Interfaces*, 2018, **10**, 34991–34999.

180 A. B. Evlyukhin, S. M. Novikov, U. Zywietz, R. L. Eriksen, C. Reinhardt, S. I. Bozhevolnyi and B. N. Chichkov, *Nano Lett.*, 2012, **12**, 3749–3755.

181 A. I. Kuznetsov, A. E. Miroshnichenko, M. L. Brongersma, Y. S. Kivshar and B. Luk'yanchuk, *Science*, 2016, **354**, aag2472.

182 S. Kruk and Y. Kivshar, *ACS Photonics*, 2017, **4**, 2638–2649.

183 C. F. Bohren and D. R. Huffman, *Absorption and scattering of light by small particles*, John Wiley & Sons, 2008.

184 N. Bontempi, K. E. Chong, H. W. Orton, I. Staude, D.-Y. Choi, I. Alessandri, Y. S. Kivshar and D. N. Neshev, *Nano-scale*, 2017, **9**, 4972–4980.

185 O. Yavas, M. Svedendahl, P. Dobosz, V. Sanz and R. Quidant, *Nano Lett.*, 2017, **17**, 4421–4426.

186 M. L. Tseng, Y. Jahani, A. Leitis and H. Altug, *ACS Photonics*, 2020, **8**, 47–60.

187 R. A. Aoni, S. Manjunath, B. I. Karawdeniya, K. Zangeneh Kamali, L. Xu, A. M. Damry, C. J. Jackson, A. Tricoli, A. E. Miroshnichenko and M. Rahmani, *Adv. Funct. Mater.*, 2022, **32**, 2103143.

188 M. Iwanaga and W. Tangkawsakul, *Biosensors*, 2022, **12**, 981.

189 M. Iwanaga, *ACS Nano*, 2020, **14**, 17458–17467.

190 H. Altug, S.-H. Oh, S. A. Maier and J. Homola, *Nat. Nanotechnol.*, 2022, **17**, 5–16.

191 Z. Wang, J. Sun, J. Li, L. Wang, Z. Li, X. Zheng and L. Wen, *Adv. Sci.*, 2023, 2206236.

192 C. W. Hsu, B. Zhen, A. D. Stone, J. D. Joannopoulos and M. Soljačić, *Nat. Rev. Mater.*, 2016, **1**, 1–13.

193 K. Koshelev, A. Bogdanov and Y. Kivshar, *Sci. Bulletin*, 2019, **64**, 836–842.

194 J. v Neumann and E. Wigner, *Phys. Z.*, 1929, **30**, 291–293.

195 Y. Jahani, E. R. Arvelo, F. Yesilkoy, K. Koshelev, C. Cianciaruso, M. De Palma, Y. Kivshar and H. Altug, *Nat. Commun.*, 2021, **12**, 3246.

196 F. Wu, D. Liu and X. Yu, *Results Phys.*, 2023, 106539.

197 C. Schiattarella, G. Sanità, B. G. Alulema, V. Lanzio, S. Cabrini, A. Lamberti, I. Rendina, V. Mocella, G. Zito and S. Romano, *Biosens. Bioelectron.*: X, 2022, **12**, 100262.

198 G. Zito, G. Sanità, B. Guilcapi Alulema, S. N. Lara Yépez, V. Lanzio, F. Riminucci, S. Cabrini, M. Moccia, C. Avitabile and A. Lamberti, *Nanophotonics*, 2021, **10**, 4279–4287.

199 L. Kühner, L. Sortino, R. Berté, J. Wang, H. Ren, S. A. Maier, Y. Kivshar and A. Tittl, *Nat. Commun.*, 2022, **13**, 4992.

200 F. Yesilkoy, E. R. Arvelo, Y. Jahani, M. Liu, A. Tittl, V. Cevher, Y. Kivshar and H. Altug, *Nat. Photonics*, 2019, **13**, 390–396.

201 L. Feng, R. El-Ganainy and L. Ge, *Nat. Photonics*, 2017, **11**, 752–762.

202 M.-A. Miri and A. Alù, *Science*, 2019, **363**, 67709.

203 J. Wiersig, *Phys. Rev. Lett.*, 2014, **112**, 203901.

204 W. Chen, Ş. Kaya Özdemir, G. Zhao, J. Wiersig and L. Yang, *Nature*, 2017, **548**, 192–196.

205 S. H. Park, S. Xia, S.-H. Oh, P. Avouris and T. Low, *ACS Photonics*, 2021, **8**, 3241–3248.

206 B. Liu, S. Zhao, X. Chen, X. Zhou, H. Zhu, F. Wang, X. Yan, T. Cheng and X. Zhang, *IEEE Sens. J.*, 2023, **23**, 11662–11671.

207 Y. Liu, P. Yan, F. Liu, A. Jian and S. Sang, *Micromachines*, 2021, **12**, 426.

208 J.-H. Park, A. Ndao, W. Cai, L. Hsu, A. Kodigala, T. Lepetit, Y.-H. Lo and B. Kanté, *Nat. Phys.*, 2020, **16**, 462–468.

209 P. Zhang, X. Zhou and S. Wang, *Chem. Methods*, 2023, e202200066.

210 G. Young and P. Kukura, *Annu. Rev. Phys. Chem.*, 2019, **70**, 301–322.

211 P. Zhang, G. Ma, W. Dong, Z. Wan, S. Wang and N. Tao, *Nat. Methods*, 2020, **17**, 1010–1017.

212 B. Špačková, H. Klein Moberg, J. Fritzsche, J. Tenghamn, G. Sjösten, H. Šípová-Jungová, D. Albinsson, Q. Lubart, D. van Leeuwen and F. Westerlund, *Nat. Methods*, 2022, **19**, 751–758.

213 E. D. Foley, M. S. Kushwah, G. Young and P. Kukura, *Nat. Methods*, 2021, **18**, 1247–1252.

214 T. Heermann, F. Steiert, B. Ramm, N. Hundt and P. Schwille, *Nat. Methods*, 2021, **18**, 1239–1246.

215 A. I. Aristov, U. Zywietz, A. B. Evlyukhin, C. Reinhardt, B. N. Chichkov and A. V. Kabashin, *Appl. Phys. Lett.*, 2014, **104**, 071101.

216 M. Autore, P. Li, I. Dolado, F. J. Alfaro-Mozaz, R. Esteban, A. Atxabal, F. Casanova, L. E. Hueso, P. Alonso-González, J. Aizpurua, A. Y. Nikitin, S. Vélez and R. Hillenbrand, *Light: Sci. Appl.*, 2018, **7**, 17172.
Review Article

Chem Soc Rev

165 V. Sreekanth, M. ElKabbash, V. Caligiuri, R. Singh, A. De Luca and G. Strangi, *New Directions in Thin Film Nanophotonics*, Springer Singapore, 2019.

166 L. Jiang, S. Zeng, Z. Xu, Q. Ouyang, D. H. Zhang, P. H. J. Chong, P. Coquet, S. He and K. T. Yong, *Small*, 2017, **13**, 1700600.

167 Y. Zou, Y. Liu and G. Song, *Sensors*, 2022, **22**, 2116.

168 F. Goos and H. Hänchen, *Ann. Phys.*, 1947, **436**, 333–346.

169 F. Goos and H. Lindberg-Hänchen, *Ann. Phys.*, 1949, **440**, 251–252.

170 X. Yin, L. Hesselink, Z. Liu, N. Fang and X. Zhang, *Appl. Phys. Lett.*, 2004, **85**, 372–374.

171 R.-G. Wan and M. S. Zubairy, *Opt. Express*, 2020, **28**, 6036–6047.

172 Z. Qin, C. Yue, Y. Lang and Q. Liu, *Opt. Commun.*, 2018, **426**, 16–22.

173 Z. Liu, F. Lu, L. Jiang, W. Lin and Z. Zheng, *Biosensors*, 2021, **11**, 201.

174 S. Zeng, G. Liang, A. Gheno, S. Vedraine, B. Ratier, H.-P. Ho and N. Yu, *Nanomaterials*, 2020, **10**, 1289.

175 Q. You, Y. Shan, S. Gan, Y. Zhao, X. Dai and Y. Xiang, *Opt. Mater. Express*, 2018, **8**, 3036–3048.

176 L. Han, J. Pan, C. Wu, K. Li, H. Ding, Q. Ji, M. Yang, J. Wang, H. Zhang and T. Huang, *Sensors*, 2020, **20**, 1028.

177 K. V. Sreekanth, Q. Ouyang, S. Han, K.-T. Yong and R. Singh, *Appl. Phys. Lett.*, 2018, **112**, 161109.

178 C.-W. Chang, X. Xu, S. Chakravarty, H.-C. Huang, L.-W. Tu, Q. Y. Chen, H. Dalir, M. A. Krainak and R. T. Chen, *Biosens. Bioelectron.*, 2019, **141**, 111396.

179 K. V. Sreekanth, W. Dong, Q. Ouyang, S. Sreejith, M. ElKabbash, C. T. Lim, G. Strangi, K.-T. Yong, R. E. Simpson and R. Singh, *ACS Appl. Mater. Interfaces*, 2018, **10**, 34991–34999.

180 A. B. Evlyukhin, S. M. Novikov, U. Zywietz, R. L. Eriksen, C. Reinhardt, S. I. Bozhevolnyi and B. N. Chichkov, *Nano Lett.*, 2012, **12**, 3749–3755.

181 A. I. Kuznetsov, A. E. Miroshnichenko, M. L. Brongersma, Y. S. Kivshar and B. Luk'yanchuk, *Science*, 2016, **354**, aag2472.

182 S. Kruk and Y. Kivshar, *ACS Photonics*, 2017, **4**, 2638–2649.

183 C. F. Bohren and D. R. Huffman, *Absorption and scattering of light by small particles*, John Wiley & Sons, 2008.

184 N. Bontempi, K. E. Chong, H. W. Orton, I. Staude, D.-Y. Choi, I. Alessandri, Y. S. Kivshar and D. N. Neshev, *Nano-scale*, 2017, **9**, 4972–4980.

185 O. Yavas, M. Svedendahl, P. Dobosz, V. Sanz and R. Quidant, *Nano Lett.*, 2017, **17**, 4421–4426.

186 M. L. Tseng, Y. Jahani, A. Leitis and H. Altug, *ACS Photonics*, 2020, **8**, 47–60.

187 R. A. Aoni, S. Manjunath, B. I. Karawdeniya, K. Zangeneh Kamali, L. Xu, A. M. Damry, C. J. Jackson, A. Tricoli, A. E. Miroshnichenko and M. Rahmani, *Adv. Funct. Mater.*, 2022, **32**, 2103143.

188 M. Iwanaga and W. Tangkawsakul, *Biosensors*, 2022, **12**, 981.

189 M. Iwanaga, *ACS Nano*, 2020, **14**, 17458–17467.

190 H. Altug, S.-H. Oh, S. A. Maier and J. Homola, *Nat. Nanotechnol.*, 2022, **17**, 5–16.

191 Z. Wang, J. Sun, J. Li, L. Wang, Z. Li, X. Zheng and L. Wen, *Adv. Sci.*, 2023, 2206236.

192 C. W. Hsu, B. Zhen, A. D. Stone, J. D. Joannopoulos and M. Soljačić, *Nat. Rev. Mater.*, 2016, **1**, 1–13.

193 K. Koshelev, A. Bogdanov and Y. Kivshar, *Sci. Bulletin*, 2019, **64**, 836–842.

194 J. v Neumann and E. Wigner, *Phys. Z.*, 1929, **30**, 291–293.

195 Y. Jahani, E. R. Arvelo, F. Yesilkoy, K. Koshelev, C. Cianciaruso, M. De Palma, Y. Kivshar and H. Altug, *Nat. Commun.*, 2021, **12**, 3246.

196 F. Wu, D. Liu and X. Yu, *Results Phys.*, 2023, 106539.

197 C. Schiattarella, G. Sanità, B. G. Alulema, V. Lanzio, S. Cabrini, A. Lamberti, I. Rendina, V. Mocella, G. Zito and S. Romano, *Biosens. Bioelectron.*: X, 2022, **12**, 100262.

198 G. Zito, G. Sanità, B. Guilcapi Alulema, S. N. Lara Yépez, V. Lanzio, F. Riminucci, S. Cabrini, M. Moccia, C. Avitabile and A. Lamberti, *Nanophotonics*, 2021, **10**, 4279–4287.

199 L. Kühner, L. Sortino, R. Berté, J. Wang, H. Ren, S. A. Maier, Y. Kivshar and A. Tittl, *Nat. Commun.*, 2022, **13**, 4992.

200 F. Yesilkoy, E. R. Arvelo, Y. Jahani, M. Liu, A. Tittl, V. Cevher, Y. Kivshar and H. Altug, *Nat. Photonics*, 2019, **13**, 390–396.

201 L. Feng, R. El-Ganainy and L. Ge, *Nat. Photonics*, 2017, **11**, 752–762.

202 M.-A. Miri and A. Alù, *Science*, 2019, **363**, eaar7709.

203 J. Wiersig, *Phys. Rev. Lett.*, 2014, **112**, 203901.

204 W. Chen, Ş. Kaya Özdemir, G. Zhao, J. Wiersig and L. Yang, *Nature*, 2017, **548**, 192–196.

205 S. H. Park, S. Xia, S.-H. Oh, P. Avouris and T. Low, *ACS Photonics*, 2021, **8**, 3241–3248.

206 B. Liu, S. Zhao, X. Chen, X. Zhou, H. Zhu, F. Wang, X. Yan, T. Cheng and X. Zhang, *IEEE Sens. J.*, 2023, **23**, 11662–11671.

207 Y. Liu, P. Yan, F. Liu, A. Jian and S. Sang, *Micromachines*, 2021, **12**, 426.

208 J.-H. Park, A. Ndao, W. Cai, L. Hsu, A. Kodigala, T. Lepetit, Y.-H. Lo and B. Kanté, *Nat. Phys.*, 2020, **16**, 462–468.

209 P. Zhang, X. Zhou and S. Wang, *Chem. Methods*, 2023, e202200066.

210 G. Young and P. Kukura, *Annu. Rev. Phys. Chem.*, 2019, **70**, 301–322.

211 P. Zhang, G. Ma, W. Dong, Z. Wan, S. Wang and N. Tao, *Nat. Methods*, 2020, **17**, 1010–1017.

212 B. Špačková, H. Klein Moberg, J. Fritzsche, J. Tenghamn, G. Sjösten, H. Šípová-Jungová, D. Albinsson, Q. Lubart, D. van Leeuwen and F. Westerlund, *Nat. Methods*, 2022, **19**, 751–758.

213 E. D. Foley, M. S. Kushwah, G. Young and P. Kukura, *Nat. Methods*, 2021, **18**, 1247–1252.

214 T. Heermann, F. Steiert, B. Ramm, N. Hundt and P. Schwille, *Nat. Methods*, 2021, **18**, 1239–1246.

215 A. I. Aristov, U. Zywietz, A. B. Evlyukhin, C. Reinhardt, B. N. Chichkov and A. V. Kabashin, *Appl. Phys. Lett.*, 2014, **104**, 071101.

216 M. Autore, P. Li, I. Dolado, F. J. Alfaro-Mozaz, R. Esteban, A. Atxabal, F. Casanova, L. E. Hueso, P. Alonso-González, J. Aizpurua, A. Y. Nikitin, S. Vélez and R. Hillenbrand, *Light: Sci. Appl.*, 2018, **7**, 17172.