tbuckley/cabot-search huggingface dataset:
A novel pathway for stemness propagation and chemoresistance in non-small cell lung cancer via phosphorylated PKM2-loaded small extracellular vesicles
Authors: Jingyi Wang, Liu Liu, Xinyu Gao, Xiyu Liu, Yitian Dai, Zijun Mao, Shengzhe Huang, Junjian Li, Dongliang Wang, Yu Qi, Yingwen Han, Yunjing Xu, Corrine Ying Xuan Chua, Alessandro Grattoni, Wenhui Xie, Hao Yang, Gang Huang
Journal: Theranostics (2025)

Rationale: Non-small cell lung cancer (NSCLC) is a predominant cause of cancer-related mortality, with its progression and treatment resistance significantly influenced by cancer stem cells (CSCs) and their complex intercellular communication mechanisms. Small extracellular vesicles (sEVs) have emerged as pivotal mediators of intercellular signaling, affecting tumor microenvironment modulation and therapeutic resistance. This study investigates the role of CSC-derived sEVs in transmitting stemness traits through the selective sorting of pyruvate kinase M2 phosphorylated at the Y105 site (pY105-PKM2), mediated by the adaptor protein IQGAP1, which supports CSC maintenance and drug resistance in NSCLC. Methods: In vitro and in vivo experiments, including proteomic and transcriptomic analyses, were conducted to identify key regulators of sEV-mediated signaling. Immunoprecipitation, proximity ligation assays, and immunofluorescence were used to examine the role of IQGAP1 in the sorting of pY105-PKM2 into sEVs. Functional assays, including sphere formation, chemoresistance tests, metabolic assessments, and cell cycle analysis, were conducted to evaluate the effects of sEV-mediated delivery of pY105-PKM2 on recipient cells. Additionally, immunohistochemistry and survival analysis were performed on tumor samples from NSCLC patients to establish clinical correlations. Results: We unveiled a novel mechanism by which CSC-derived sEVs transmit stemness traits to replenish the CSC pool in NSCLC. CSC-derived sEVs were enriched with pY105-PKM2, correlating with enhanced stemness, chemoresistance, and poor clinical outcomes. Mechanistically, IQGAP1 was identified as an adaptor facilitating the selective sorting of pY105-PKM2 into sEVs through interactions with the ESCRT component TSG101. Recipient cells treated with CSC-derived sEVs exhibited metabolic reprogramming, slower cell cycle progression, and enhanced chemoresistance. The synergistic role of IQGAP1 and pY105-PKM2 was confirmed, highlighting their critical contributions to CSC maintenance and malignant progression. Conclusion: This study highlights the critical role of CSC-derived sEVs in NSCLC progression and therapy resistance through the IQGAP1-mediated selective sorting of pY105-PKM2. By uncovering this novel pathway, our findings provide valuable insights into CSC pool replenishment and therapeutic resistance mechanisms in NSCLC, identifying IQGAP1 and pY105-PKM2 as promising therapeutic targets for mitigating CSC-driven malignancy and enhancing treatment efficacy.
CD19-targeted HSP90 inhibitor nanoparticle combined with TKIs reduces tumor burden and enhances T-cell immunity in murine B-cell malignancies
Authors: Mengting Qin, Juan Ren, Xiaodong Chen, Wen Zhou, Shuyuan Zhang, Weile Zhang, Mengxin Shi, Mingzhen Zhang, Huashen Liu, Yunfeng Ma, Mei Yang, Yanhong Ji
Journal: Theranostics (2025)

Rationale: Conventional chemotherapies for B-cell malignancies are often limited by drug resistance and significant side effects due to non-specific targeting. This research aimed to improve treatment efficacy by developing nano-delivery systems that specifically target tumor cells, thereby enhancing therapeutic precision and reducing off-target toxicity. Methods: The construction, biocompatibility, and targeting capability of CD19@NP/17-DMAG were evaluated using TEM, HPLC, FTIR spectroscopy, CCK-8 assay, flow cytometry (FC), and IVIS imaging. Therapeutic efficacy was assessed through Western blotting, RT-qPCR, flow cytometry, H&E staining, BrdU assay, and apoptosis assays. The mechanism of action of CD19@NP/17-DMAG in murine B-cell malignancies was investigated using RNA sequencing, in vivo T-cell depletion, and CRISPR/Cas9 technology. Results: CD19@NP/17-DMAG nanoparticles demonstrated enhanced efficacy in murine models of BCR-ABL1⁺ B-cell acute lymphoblastic leukemia (B-ALL) when combined with tyrosine kinase inhibitors (TKIs), including the BCR-ABL1-targeted imatinib and the broad-spectrum ponatinib. This combination significantly reduced tumor burden, prolonged survival, and induced a robust anti-tumor T-cell response. RNA-seq analysis indicated that the targeted treatment modulated genes related to cell proliferation, apoptosis, and antigen presentation. Notably, this treatment also increased MHC class I (MHC-I) expression, thereby strengthening antigen presentation in BCR-ABL1⁺ B-ALL cells. Ponatinib-based therapy achieved complete remission, eradicated minimal residual disease, and established long-term immune memory in BCR-ABL1⁺ B-ALL. In addition, CD19@NP/17-DMAG was effective in another B-cell malignancy model, A20 lymphoma, significantly slowing tumor growth and amplifying T-cell responses. Conclusions: These findings highlight the CD19@NP/17-DMAG system as a promising therapeutic approach that both augments T cell immune responses and minimizes side effects in B-cell malignancies.
Photoactivatable immunomodulator polyprodrugs for boosting synergistic antitumor immunity of STING agonists and IDO inhibitors
Authors: Guopu Huang, Cheng Li, Jiale Si, Yufei Cao, Moujiang Zheng, Yueming Xue, Qinghao Zhou, Zhishen Ge, Yuanyuan Ji
Journal: Theranostics (2025)

Rationale: Stimulator of interferon genes (STING) activation within tumors can inevitably enhance the activity of indoleamine 2,3-dioxygenase (IDO). However, IDO will convert tryptophan (Trp) into kynurenine (Kyn), which can inhibit Trp-sensitive T cells functional activity and induce immunosuppressive effects. The efficient nanomedicines for combination of STING agonist and IDO inhibitor have been rarely explored. Methods: A diblock polymer polyprodrug was synthesized with the IDO inhibitor 1-methyl-tryptophan (1-MT) linked by thioketal bonds and the photosensitizer 5,10,15,20-tetraphenylporphyrin (TPP) in the hydrophobic block as well as endoplasmic reticulum (ER) targeting group (4-methylphenyl) sulfonamide in the hydrophilic block. After self-assembly in aqueous solution, the micelles loading STING agonist SR-717 (SR@ET-PMT) can be formed with a high loading efficiency. After cellular internalization, the micelles can target ER. Upon exposure to light irradiation of 650 nm, reactive oxygen species (ROS) can be generated to break thioketal bonds and dissociate the micelles to release 1-MT and STING agonist. Accompanied by photodynamic therapy (PDT), STING activation and IDO inhibition are achieved simultaneously. Results: In vitro observation reveals the PDT effect, ER targeting, and photoactivated drug release. In vivo animal model results demonstrate that the photoactivatable immunomodulator polyprodrug micelles show excellent tumor accumulation and potent immune activation capability to inhibit solid tumors. The PDT effect, STING activation, and IDO inhibition synergistically activate in vivo antitumor immunity. Finally, SR@ET-PMT can attain an 88% suppression rate of solid tumors due to the potent immunotherapeutic efficacy. Conclusion: The photoactivatable immunomodulator polyprodrugs are successfully prepared to simultaneously deliver STING agonists and IDO inhibitors, which represent a promising nanomedicine for the spatiotemporal activation of synergistic antitumor immunity.
Investigating the relationships of structural and functional neural networks of primary visual cortex with engineered AAVs and chemogenetic-fMRI techniques
Authors: Zhu Gui, Kunzhang Lin, Nengsong Luo, Zengpeng Han, Zhuang Liu, Ziyue Zhao, Lei Gu, Fanyong Xu, Ning Zheng, Fuqiang Xu, Xihai Li, Jie Wang
Journal: Theranostics (2025)

Rationale: Neural networks are crucial for brain function, but the relationship between functional and structural networks remains unclear, hindering disease understanding and treatment. This study employs AAVs, MRI reporter gene (AQP1), and chemogenetic-fMRI to explore the relationship between structural and functional connectivity in the mouse primary visual cortex (V1), offering a novel approach to study abnormal brain functions. Methods: The rAAV-PHP.eB-DIO vector encoding AQP1 was used to cross the blood-brain barrier and infect the brain, enabling in vivo diffusion-weighted imaging (DWI-MRI) to assess the anterograde structural connectivity network of V1. Additionally, chemogenetic activation of V1 using a Cre-dependent system was performed, and the whole-brain BOLD responses were evaluated using fMRI. The integration of these techniques provided a comprehensive analysis of the relationship between functional and structural connectivity. Results: This study successfully achieved the combined detection of structural and functional connectivity in the V1 of mice. The rAAV1-hSyn-Cre virus was utilized for monosynaptic anterograde tracing. Additionally, a blood-brain barrier-crossing serotype viral vector, rAAV-PHP.eB-DIO-AQP1-EGFP, was intravenously injected to effectively transduce AQP1 into the V1 region and its downstream areas. The results indicated that regions expressing AQP1 under the control of Cre recombinase, including V1, LGN, CPu, and SC, exhibited significant alterations in DWI signal intensity (SI) and apparent diffusion coefficient (ADC). DREADD-fMRI analysis revealed that chemogenetic activation of the V1 region significantly enhanced neural activity in related brain regions, accompanied by a notable increase in BOLD signals. These regions included CPu, HIP, TH, SC, and PAG. Conclusion: In vivo decoding of neuronal activity and structural connectivity provides insights into brain structure-function interplay, which was important for understanding the cerebral function.
Circular RNA CHACR is involved in the pathogenesis of cardiac hypertrophy
Authors: Lili Chen, Wenjing Wang, Yiheng Zhao, Shuchen Zhang, Xiang Zhou
Journal: Theranostics (2025)

Background: Circular RNAs (circRNAs) exhibit differential expression in cardiac hypertrophy; however, their functions and mechanisms remain largely unexplored. This study aimed to determine the involvement of circRNAs in the pathogenesis of myocardial hypertrophy. Methods: A mouse model of cardiac hypertrophy was established using transverse aortic constriction (TAC) and differentially expressed circRNAs were identified via high-throughput sequencing. To facilitate gene overexpression or knockdown, related viruses were injected into myocardial tissues of the mice. Cardiomyocyte hypertrophy was assessed using quantitative real-time PCR and immunofluorescence staining. RNA immunoprecipitation, RNA pull-down assay and fluorescence in situ hybridization were conducted to confirm the interaction between circRNAs and proteins. Protein expression and degradation were evaluated using cycloheximide-chase assay, immunoprecipitation, and western blotting. Results: Cardiac hypertrophy-associated circRNA (CHACR) was significantly downregulated in myocardial tissues from TAC mice. CHACR can attenuate cardiac hypertrophy through upregulating carnitine palmitoyltransferase-1b (CPT1b) expression. Mechanistically, CHACR directly interacted with CPT1b and decreased its protein degradation by inhibiting the ubiquitin-proteasome pathway to increase its expression in cardiomyocytes. Moreover, CPT1b overexpression decreased L-carnitine levels and inhibited the Jak2/Stat3 signaling pathway, which was associated with the pathogenesis of myocardial hypertrophy. Conclusions: CHACR attenuated cardiomyocyte hypertrophy by facilitating the expression of CPT1b, which plays a role in regulating the Jak2/Stat3 pathway via L-carnitine. CHACR may thus be a potential therapeutic target for pathological myocardial hypertrophy.
Time for action: actinium-225 PSMA-targeted alpha therapy for metastatic prostate cancer - a systematic review and meta-analysis
Authors: Gaia Ninatti, Pietro Scilipoti, Cristiano Pini, Francesco Barletta, Mattia Longoni, Fabrizia Gelardi, Martina Sollini, Giorgio Gandaglia, Mike Sathekge, Francesco Montorsi, Arturo Chiti, Alberto Briganti
Journal: Theranostics (2025)

Rationale: Metastatic prostate cancer in the castration-resistant (mCRPC) setting remains challenging to treat. Prostate-specific membrane antigen (PSMA)-targeted alpha therapy (TAT) is emerging as a promising option. We aimed to systematically review the efficacy and safety of PSMA-TAT in patients with prostate cancer. Methods: A comprehensive search of PubMed/MEDLINE and EMBASE databases was conducted up to October 2024, adhering to the PRISMA guidelines. Selected studies were original research articles evaluating the efficacy and/or safety of PSMA-TAT including at least 10 patients. The outcomes measured included any prostate-specific antigen (PSA) response, ≥50% PSA reduction (PSA50), progression-free survival (PFS), overall survival (OS), and adverse events. PSA50 was pooled using a random-effects model, incorporating individual patient data on PSA50 and previous lines of treatment. Results: Eighteen studies involving 1,155 patients met the inclusion criteria. The majority included heavily pre-treated patients. The most commonly employed radiopharmaceutical was [225Ac]Ac-PSMA-617, in 15 studies. The pooled PSA50 response rate was 65% [95% Confidence interval (CI), 57-72%] with a moderate level of heterogeneity (I² = 81.17%, p < 0.001). Pooled response rates in patients who received none, one, and more than one prior line of treatment were 82% (95% CI, 73-90%), 72% (95% CI, 56-85%), and 55% (95% CI, 48-63%), respectively. PFS varied from 3 to 15 months, and OS from 8 to 31 months. Adverse events were predominantly mild (grades 1-2); severe adverse events (≥ grade 3) included anaemia (11%) and thrombocytopenia (6%). Conclusion: PSMA-TAT holds promising efficacy and an acceptable safety profile for treating metastatic prostate cancer. Randomised controlled trials are needed to optimise treatment protocols toward the implementation of PSMA-TAT into clinical practice.
A self-healing radiopaque hyaluronic acid hydrogel as a new injectable biomaterial for precision medicine in osteoarthritis
Authors: Moustoifa Said, Clément Tavakoli, Chloé Dumot, Karine Toupet, Cécile Olivier, Alexia Gilles, Marie Maumus, Yuxi Clara Dong, Nora Collomb, Céline Auxenfans, Anaïck Moisan, Bertrand Favier, Benoit Chovelon, Emmanuel Luc Barbier, David Peter Cormode, Emmanuel Brun, Hélène Elleaume, Marlène Wiart, Olivier Detante, Claire Rome, Danièle Noël, Rachel Auzély-Velty
Journal: Theranostics (2025)

Rationale: Osteoarthritis (OA) is a degenerative disease affecting cartilage, synovium and bone, that is a major cause of pain and disability. Intra-articular injection of hyaluronic acid (HA) derivatives, also known as viscosupplementation (VS), is a common treatment for the symptomatic management of knee OA. Despite its widespread use, the magnitude of the clinical benefit of VS remains controversial, with conflicting results due to methodological differences and possible differences in efficacy between products related to remanence and rheological properties. Methods: Here, to create an effective HA-based treatment, an injectable self-healing HA hydrogel with long-persistent radiopacity is formed by tethering a clinical iodine contrast agent to HA. The labeling conditions are tuned to obtain sufficient X-ray signal without altering the biocompatibility, rheological and injectability properties of the hydrogel. Results: The iodine labeling enabled to monitor not only delivery of the hydrogel but also its retention in mouse knees up to 5 weeks post-administration using synchrotron K-edge subtraction-computed tomography. We further demonstrated that the unique properties of this hydrogel enable creation of a transient HA network in vivo that attenuates OA progression in a mouse model of OA. Moreover, our data showed that the rate of HA-I disappearance appears to predict treatment response, likely because a rapid elimination serves as an indirect indicator of in situ inflammation. Conclusion: Collectively, these results show that our radiopaque HA-I hydrogel holds significant promise for improving patient management in the treatment of OA before clinical symptoms worsen. Its capacity for in vivo tracking over time allows for personalized treatment schedules based on observed retention and therapeutic effect. As a result, this theranostic hydrogel emerges as a strong candidate for precision medicine in OA.
Mechanisms and novel therapeutic roles of bitter taste receptors in diseases
Authors: Aiyang Tong, Hongyu Yang, Xiaohui Yu, Dongkai Wang, Jian Guan, Ming Zhao, Ji Li
Journal: Theranostics (2025)

Bitter taste receptors (TAS2R) are expressed in the oral cavity, intestine, airways, and vascular smooth muscle, where they regulate physiological processes, including immune responses. However, the activation of TAS2R triggers signaling pathways that influence inflammation, metabolism, and cell proliferation, suggesting their potential as therapeutic targets for diseases such as Alzheimer's disease, Parkinson's disease, asthma, and cancer. Bitter compounds capable of activating TAS2R have shown potential in modulating these pathways, presenting novel opportunities for drug development. This review examines the expression of TAS2R across diverse tissues, their complex physiological roles, and potential therapeutic applications, including disease management and targeted drug delivery.
Drugless peptide-based nanohybrids alleviate diabetic retinopathy by suppressing microglial activation and endothelial inflammation
Authors: Mei Du, Xiao Zhao, Miao Guo, Xiaoyu Wang, Yutian Zhang, Linshan Yang, Sixia Liu, Liya Sun, Mengyu Liao, Xue Dong, Yi Lei, Yumeng Zhao, Shuqi Liang, Xiaohong Wang, Caiyun You, Hong Yang, Hua Yan
Journal: Theranostics (2025)

Background: Diabetic retinopathy (DR) is a vision-threatening microvascular complication of diabetes mellitus. Chronic inflammation and endothelial dysfunction are critical factors in the disease's pathogenesis. Consequently, interventions developed to reduce retinal inflammation are anticipated to be beneficial for both the prevention and treatment of DR. In the present study, we developed a unique class of drugless peptide-based nanohybrids with potent anti-inflammatory activities and investigated their therapeutic efficacy for treating DR in an oxygen-induced retinopathy (OIR) mouse model and a streptozotocin (STZ)-induced diabetic mouse model. Methods: Hexapeptides were applied to modify gold nanoparticles to form the drugless peptide-based nanohybrids (P12). We then examined the physicochemical properties and anti-inflammatory activities of P12 in HUVECs and BV2 cells and identified the critical amino acids for this novel bioactivity. The intravitreal and retro-orbital injections were applied to determine the optimal retinal delivery route for P12. The therapeutic efficacy of P12 in treating DR were investigated using both the OIR model and STZ-induced diabetic model. Through immunohistochemistry and flow cytometry analyses, we identified the major cells that internalize P12 in the retina. Furthermore, in vitro experiments were used to explore the underlying molecular mechanisms for the anti-inflammatory activities of P12. Results: We found that P12 exhibited potent anti-inflammatory effects in both HUVECs and BV2 cells. In addition, P12 can be efficiently delivered to the retina via intravitreal injection. Intravitreally injected P12 significantly improved early DR symptoms including vascular leakage and pericyte loss in STZ-induced diabetic mice. It also suppressed pathological neovascularization and retinal hemorrhage in OIR mice. Importantly, we found that intravitreally injected P12 was mainly taken up by microglial and endothelial cells, leading to reduced retinal endothelium inflammation and microglial activation in DR animal models. Mechanistic studies revealed that P12 potently inhibited several TLR4 downstream signaling pathways, such as NF-κB, JNK, and P38 MAPK, in both endothelial and microglial cells. This effect is due to the capacity of P12 in blocking the endosomal acidification process that governs the endosomal TLR signaling transduction. Conclusions: Our findings suggest that local injection of properly designed, drugless, peptide-based nanohybrids can serve as a safe and effective anti-inflammatory nanomedicine for treating DR.
Modulation of comorbid depression of neuropathic pain by dopamine input from VTA to the ventral hippocampus
Authors: Yuanyuan Ji, Yifan Xiao, Xiaoyan Bai, Junxiang Gu, Teng Ma, Yue Feng, Jian Wang, Yupeng Feng, Tao Chen, Jianghua Lai, Juan Shi, Jinlian Li
Journal: Theranostics (2025)

Background: Chronic pain syndrome is a devastating disorder with poor clinical treatment. The circuitry and molecular mechanisms for depression comorbid with chronic pain are thus far unclear. We characterized the projection from the ventral tegmental area (VTA) to the ventral hippocampus (vHPC) and assessed the functional significance of the pathway in chronic pain-induced depressive comorbidity. Methods: A neuropathic cuff model was adopted and discriminated against the susceptible and resilient groups with or without depression-like behaviors, respectively. The anatomical feature and function of the VTA-vHPC pathway were assessed by tracer and virus-based tracing, immunofluorescent staining, fluorescence in situ hybridization (FISH), designer receptors exclusively activated by designer drugs (DREADDs), optogenetics, and ex vivo electrophysiology. Results: A group of medially-located dopaminergic (DAergic) neurons displayed few overlappings with the medial prefrontal cortex- or nucleus accumbens-projecting neurons, constituting the major projection from the VTA to the vHPC. The activity of vHPC-projecting DAergic neurons was downregulated in the susceptible group but not in the resilient group, as manifested by the decreased expression of tyrosine hydroxylase (TH), TH/FOS double-labeling, and excitability in retrogradely labeled VTA neurons. Chemogenetic activation of the pathway significantly improved depression rather than pain phenotype, but caspase 3-based ablation induced depression. Optogenetic activation of the VTADA-vHPC pathway produced similar anti-depressant effects in cuff animals in an equally D1 or D2 receptor-dependent manner. FISH and Western blotting disclosed a low-segregated expression of the D1 receptor in the pyramidal neurons and a highly-segregated expression of the D2 receptor in GABAergic neurons in vHPC, which underwent no change or upregulation following cuffing. Conclusion: Our results demonstrate a medially dominant VTADA projection to the vHPC. Reinforcement of this pathway can reverse the depression without affecting pain, thus providing insights into a connectivity-based strategy in the treatment of comorbid depression.