tbuckley/cabot-search huggingface dataset:
Promotion of Cx26 mutants located in TM4 region for membrane translocation successfully rescued hearing loss
Authors: Yan-Jun Zong, Xiao-Zhou Liu, Xin-Yu Shi, Zheng-Dong Zhao, Yu Sun
Journal: Theranostics (2025)

Rationale: The GJB2 gene, which encodes connexin 26 (Cx26), is recognized as the leading cause of non-syndromic hereditary hearing loss. In clinical settings, a total of 131 Cx26 mutations have been identified in association with hearing loss. Certain Cx26 mutants display normal structural and functional properties but fail to translocate to the plasma membrane. Enhancing the membrane localization of these mutants may provide a promising strategy for rescuing hearing loss and hair cell degeneration. Methods: This study investigated the membrane localization of Cx26 using in vitro cell lines, cultured cochlear explants, and in vivo murine models. Key proteins involved in the membrane localization of Cx26 were identified and validated through immunoprecipitation-mass spectrometry (IP-MS) and co-immunoprecipitation (Co-IP). Additionally, cell lines and murine models harboring Cx26 mutants were developed to evaluate the effects of Narciclasine on enhancing the membrane localization of these mutants, as well as its potential to rescue hearing loss. Results: The membrane localization of Cx26 was dependent on the integrity of the intracellular transport network consisting of microtubules, actin microfilaments, and the Golgi apparatus. Additionally, SPTBN1 played a significant role in this process. The transmembrane domain 4 (TM4) region exhibited a strong association with the membrane localization of Cx26, and Cx26 mutants located in TM4 region retained in the cytoplasm. Narciclasine promoted cytoskeletal development, thereby enhancing the membrane localization of Cx26 mutants retained in the cytoplasm. This process helped to reconstruct the inner ear gap junction network and rescue hearing loss and hair cell degeneration. Conclusion: These findings present that enhancing the membrane localization of Cx26 mutants can significantly improve auditory function. This strategy offers a potential therapeutic approach for addressing hereditary sensorineural hearing loss associated with GJB2 mutations.
ATP released by ultrasound targeted microbubble cavitation induces vascular inflammation and improves immune checkpoint blockade efficacy
Authors: Sepideh Jahangiri, Samuel Bourdages, Emma Skora, John Stagg, François Yu
Journal: Theranostics (2025)

Rationale: Extracellular ATP (eATP) is a potent immune stimulant that functions as a damage-associated molecular pattern. The regulation of eATP is primarily mediated by cell surface ecto-nucleotidases (CD39 and CD73) which hydrolyze ATP into adenosine, a potent immune suppressor. CD39 and CD73 are upregulated in most cancers. Therapeutic strategies aimed at increasing ATP release in the tumor microenvironment or inhibiting adenosine activity are active areas of research in immuno-oncology. Ultrasound-Targeted Microbubble Cavitation (UTMC) is an externally applied, spatially targeted approach that has demonstrated synergy with immune checkpoint blockade (ICB) in solid tumors. However, the underlying mechanisms and optimal therapeutic combinations remain under investigation. We hypothesized that modulating purinergic signaling by UTMC could further leverage ICB efficacy. Methodologies: Here, we investigated non-ablative and flow-preserving UTMC to enhance ATP release and induce inflammatory responses in a murine syngeneic colorectal tumor model (MC38) with and without CD39 inhibition. We compared two UTMC pressures (400 and 850 kPa), evaluating their impact on tumor blood flow by contrast perfusion imaging, their ability to release ATP using bioluminescence, their effect on vascular inflammation and cancer cell death through histological analysis, their synergy with aPDL1 to improve ICB efficacy, immune cell infiltration to the tumor, and immune cell drainage to the tumor-draining lymph nodes (TDLN). Results: UTMC at 850 kPa and in CD39 knockout model released higher eATP concentrations, which correlated with increased vascular inflammation, enhanced cancer cell death, and reduced cancer cell proliferation. The combination of aPDL1 with UTMC and CD39 blockade significantly reduced tumor growth. This treatment also increased cytotoxic T cells (CTL), the CTL/Treg ratio, dendritic cells, and M1-prototype tumor-associated macrophages, while reducing M2-prototype macrophages within the tumor. In the TDLNs, the fully combined treatment elevated CTLs, dendritic cells, and M1-prototype macrophages, with a concurrent reduction in M2-prototype macrophages. Conclusion: Our findings support that purinergic signaling can be leveraged in combination with UTMC to improve ICB therapy.
Polyphenol and metal ion-reinforced supermolecular hydrogels incorporating nanofiber drug and peptide for annulus fibrosus regeneration
Authors: Long Xin, Xiaolin Li, Yang Yang, Pan Chen, Yi Li, Jianhua Liu, Kangbo Chen, Peipei Su, Shuaishuai Feng, Shiping He, Xinwei Xu, Wei Wang, Weixing Xu
Journal: Theranostics (2025)

Rationale: Following the structural destruction of annulus fibrosus (AF), the early-stage damage manifests as symptoms such as an inflammatory phenotype and loss of mechanical support. The microenvironmental deterioration at the injury site, the limited population, and the inadequate differentiation of intrinsic stem/progenitor cells impede the efficient repair of AF. To address the aforementioned challenges, we developed a dual-drug-loaded hydrogel system to achieve systematic and functional annulus fibrosus tissue repair. Methods: A tannic acid-crosslinked gelatin-based hydrogel scaffold with the addition of Mn2+ was designed to work as a platform to provide mechanical support, antioxidant capacity, and immune-modulating function. The kartogenin-loaded nanofiber and SDF-1α mimic peptide were also incorporated into the hydrogel system to facilitate the recruitment of endogenous stem cells and direct AF tissue regeneration. Results: The resulting hydrogel scaffolds exhibit excellent biogenic properties while achieving mechanical properties similar to those of AF. The composite scaffold also enhances ROS clearance and promotes M2 polarization of macrophages to improve the inflammatory microenvironment during early-stage injury. Furthermore, the sustained release of kartogenin-loaded nanofiber and SDF-1α mimic peptide effectively enhances endogenous stem cell recruitment, promotes cartilage differentiation, and facilitates specific extracellular matrix deposition, thus meeting requirements for late-stage AF repair. Conclusion: The findings demonstrate the potential of a multifunctional, high-strength supramolecular hydrogel loaded with dual drugs for the functional regeneration of AF tissue.
GPX4 knockdown suppresses M2 macrophage polarization in gastric cancer by modulating kynurenine metabolism
Authors: Jingli Xu, Chunyan Weng, Yanqiang Zhang, Qianyu Zhao, Jiahui Chen, Siwei Pan, Yan Wang, Ruolan Zhang, Yuqi Wang, Weiwei Zhu, Mengxuan Cao, Dan Zu, Shengjie Zhang, Zhiyuan Xu, Can Hu, Xiangdong Cheng
Journal: Theranostics (2025)

Background: Glutathione peroxidase 4 (GPX4), an important factor regulating redox homeostasis, plays an important role in tumor microenvironment and progression. However, the role of GPX4 in gastric cancer (GC) is unclear. Methods: Spectral flow cytometry and multiplex immunohistochemistry were employed to assess the correlation between GPX4 expression and immune cell infiltration. Metabolomics analysis of conditioned media from GPX4 knockdown NUGC3 cells identified metabolic alterations. Additionally, both in vitro and in vivo functional studies were conducted to elucidate the mechanistic role of GPX4 in regulating the tumor microenvironment and progression. Results: Knockdown of GPX4 in GC cells inhibited tumor growth, enhanced CD8+ T cell infiltration, and suppressed the polarization of tumor-associated macrophages (TAMs) toward the pro-tumor M2 phenotype. Multiplex immunohistochemistry revealed a positive correlation between GPX4 expression and M2 macrophage infiltration in clinical samples from patients with GC. Metabolomics revealed that GPX4 knockdown regulate kynurenine metabolism pathway. Furthermore, mechanistic studies reveal that GPX4 silencing elevates lipid peroxidation, triggering the conversion of KYNU ubiquitin chain modifications from K48 to K63. Such ubiquitination remodeling stabilizes KYNU expression (a key kynurenine-metabolizing enzyme), reduces kynurenine accumulation, and ultimately reprograms TAM polarization to enhance antitumor immunity. We also identified that the K96 and K163 sites are important for KYNU's modification by K48 and K63 ubiquitin chains. Conclusion: Our study not only affirm the role of GPx4 in GC progression but also highlight it as a promising target for reshaping the immune microenvironment.
Targeting the STING pathway in tumor-associated macrophages regulates innate immune sensing of gastric cancer cells: Erratum
Authors: Lei Miao, Jingjing Qi, Qi Zhao, Qi-Nian Wu, Da-Liang Wei, Xiao-Li Wei, Jia Liu, Jun Chen, Zhao-Lei Zeng, Huai-Qiang Ju, Hui-Yan Luo, Rui-Hua Xu
Journal: Theranostics (2025)

[This corrects the article DOI: 10.7150/thno.37745.].
Image-guided Pro-angiogenic Therapy in Diabetic Stroke Mouse Models Using a Multi-modal Nanoprobe: Erratum
Authors: Ying-Ying Bai, Xihui Gao, Yuan-Cheng Wang, Xin-Gui Peng, Di Chang, Shuyan Zheng, Cong Li, Shenghong Ju
Journal: Theranostics (2025)

[This corrects the article DOI: 10.7150/thno.9525.].
A bifunctional fusion membrane-based biocompatible nanovaccine to potentiate cancer immunotherapy
Authors: Wei Fu, Xing Cai, Jinru Yang, Lian Yang, Yaoyu Pan, Zhan Tuo
Journal: Theranostics (2025)

Background: Cancer cell membrane-based nanovaccines derived from patients' tumor tissues have shown promising features as a personalized cancer treatment strategy. However, the weak immunogenicity of autologous tumor antigens undermines the therapeutic effects of personalized vaccines. Methods: We synthesized a biomimetic nanovaccine, Bio-HCP@FM-NPs, composed of senescent tumor cell membranes, Escherichia coli cytoplasmic membrane extracts, and granulocyte-macrophage colony-stimulating factor (GM-CSF)-encapsulated biocompatible hypercross-linked polymer nanoparticles. The nanovaccine's antitumor and enhanced immunotherapy effects were demonstrated in multiple tumor models. The tumor prevention effects of nanovaccine were assessed using a postoperative recurrence model. Results: The Bio-FM@HCP-NP vaccine showed promising therapeutic efficacy in the B16-F10 melanoma mouse model and significantly synergized with anti-PD-1 immunotherapy across multiple tumor models. Mechanistically, GM-CSF was promptly released to recruit naïve DCs to the nanovaccine. Thereafter, immature DCs were vigorously activated by FM-NPs, thereby activating the cytotoxic T cells. Furthermore, Bio-HCP@FM-NPs induced robust antigen-specific immune responses, prolonging postoperative survival in mice and providing long-term protection against tumor recurrence. Targeted depletion of immune cell populations revealed that T and B cells were essential for vaccine-induced tumor regression. Conclusion: The Bio-HCP@FM-NPs showed significant promise for immunotherapy and tailored postoperative treatment of cancer, leveraging the strong activation of innate immunity by senescent tumor cell membranes and bacterial cytoplasmic membrane extracts.
Exosomes: innovative biomarkers leading the charge in non-invasive cancer diagnostics
Authors: Jiale Li, Ailin Wang, Haijun Guo, Wei Zheng, Rui Chen, Changfeng Miao, Dandan Zheng, Jun Peng, Jiachong Wang, Zigui Chen
Journal: Theranostics (2025)

Exosomes, nanoscale extracellular vesicles secreted by diverse cell types, have emerged as promising biomarkers for non-invasive tumor diagnostics, offering significant advantages over traditional methods. These vesicles, typically ranging from 30 to 150 nanometers in size, carry a diverse cargo of proteins, lipids, RNA, and microRNAs, which reflect the molecular alterations occurring within their parent cells. Notably, exosomes can be isolated from easily accessible biofluids such as blood, urine, and saliva, making them ideal candidates for liquid biopsy applications. This review explores the transformative potential of exosome-based biomarkers in the early detection and monitoring of cancers across diverse organ systems, including respiratory, digestive, hematological, neurological, endocrine malignancies and so on. Special emphasis is placed on their application in clinical trials, where exosome-based diagnostics have demonstrated promising results in detecting tumors at early stages and monitoring treatment responses, offering a less invasive and more accessible alternative to traditional biopsies. While recent advancements in exosome isolation and characterization technologies have significantly improved the sensitivity and specificity of these diagnostics, challenges such as biological heterogeneity, lack of standardization, and regulatory hurdles remain. Nevertheless, exosome-based diagnostics hold the promise of providing real-time, dynamic insights into tumor progression, enhancing personalized medicine. The integration of exosomes into clinical practice could revolutionize cancer diagnostics and therapy, improving patient outcomes. Further research and large-scale clinical validation are essential to fully realize the clinical potential of exosome-based biomarker applications in routine clinical settings.
Mechanism of valproic acid-induced hepatic steatosis via enhancing NRF2-FATP2-mediated fatty acid uptake
Authors: Xiaoliang He, Rui Yuan, Ying Chen, Wenni Huang, Zihao Xu, Bixia Wang, Changhui Liu, Tianqin Xiong
Journal: Theranostics (2025)

Rationale: Valproic acid (VPA), a first-line antiepileptic drug, can induce life-threatening hepatic steatosis with prolonged use; however, the underlying mechanisms remain inadequately elucidated. Nuclear factor E2-related factor 2 (NRF2) is a hepatoprotective factor that maintains redox homeostasis; however, increased levels have been observed in VPA-induced hepatic steatosis. Therefore, the present study aimed to investigate the function of NRF2 in VPA-triggered hepatic steatosis. Methods: NRF2 overexpression mice, NRF2 knockout mice, and fatty acid transport protein 2 (FATP2) knockout mice were constructed using adeno-associated virus, homologous recombination, and CRISPR/Cas9 technology, respectively. The mice were then treated with or without oral VPA to induce hepatic steatosis. Results: NRF2 nuclear expression was positively correlated with triglyceride levels in VPA-induced hepatic steatosis. NRF2 overexpression exacerbated VPA-triggered inflammation and steatosis, whereas NRF2 knockout alleviated the effects. Chromatin immunoprecipitation and dual-luciferase reporter gene assay confirmed that FATP2 is a target gene of NRF2. NRF2 exacerbated VPA-induced hepatic steatosis dependent on FATP2. VPA bound to Cys288 and Arg415 of Kelch-like ECH-associated protein 1 (KEAP1), leading to its autophagic degradation and subsequent nuclear translocation of NRF2. Conclusions: Our results revealed a mechanism that VPA binds to specific KEAP1 sites, promoting its degradation and disrupting the KEAP1-NRF2 complex, thereby facilitating NRF2 nuclear translocation. Subsequently, NRF2 activates FATP2 transcription, enhancing fatty acid uptake and contributing to hepatic steatosis. Our findings suggest that inhibiting the NRF2-FATP2 axis could improve VPA-induced hepatic steatosis, offering promising insights into managing drug-induced fatty liver disease.
Wnt5a induces ROR1 dependent NF-κB activation to enhance MMP-9 expression and invasiveness in chronic lymphocytic leukemia
Authors: Md Kamrul Hasan, George F Widhopf Ii, Emanuela M Ghia, Thomas J Kipps
Journal: Leukemia (2025)

Abstract Matrix metalloproteinase-9 (MMP-9) facilitates the extravasation and lymphoid-tissue infiltration of chronic lymphocytic leukemia (CLL) cells. Prior studies found that high level expression of MMP-9 in CLL associates more aggressive disease. We find that circulating CLL cells that express high levels the onco-embryonic protein ROR1 express significantly higher levels of MMP-9. Stimulation of CLL cells with Wnt5a could enhance expression and the release of MMP-9 into the culture media and increase the capacity of CLL cells to invade Matrigel in a Boyden-Chamber Assay. Such effects of Wnt5a could not be inhibited by BTK inhibitors such as ibrutinib or zanubrutinib, but could be blocked by zilovertamab, a humanized mAb specific for ROR1. We found that siRNA silencing of NF-κB-p65 or use of an NF-κB inhibitor (CAS 545380-34-5) blocked the capacity of Wnt5a to induce MMP-9 or enhance the invasive capacity of treated CLL cells. Moreover, siRNA directed silencing of MMP9 or treatment with an MMP-9 inhibitor (CAS 1177749-58-4) also blocked the invasive capability of CLL cells induced by Wnt5a. We conclude that Wnt5a-induced ROR1-signaling can induce expression of MMP-9 on CLL cells through activation of NF-κB, thereby enhancing the extravasation and lymphoid-tissue infiltration required for CLL cell trafficking.
Integrated cascade antioxidant nanozymes-Cu<sub>5.4</sub>O@CNDs combat acute liver injury by regulating retinol metabolism
Authors: Jiayu Chen, Yujie Zhang, Zhichao Deng, Yuanyuan Zhu, Chenxi Xu, Bowen Gao, Wenlong Wang, Jie Xiao, Zhengtao Xiao, Mingzhen Zhang, Kangsheng Tu
Journal: Theranostics (2025)

Background: Acute liver failure (ALF) represents a critical medical condition marked by the abrupt onset of hepatocyte damage, commonly induced by etiological factors such as hepatic ischemia/reperfusion injury (HIRI) and drug-induced hepatotoxicity. Across various types of liver injury, oxidative stress, heightened inflammatory responses, and dysregulated hepatic retinol metabolism are pivotal contributors, particularly in the context of excessive reactive oxygen species (ROS). Methods: C-dots were combined with Cu5.4O USNPs to synthesize a cost-effective nanozyme, Cu5.4O@CNDs, which mimics the activity of cascade enzymes. The in vitro evaluation demonstrated the ROS scavenging and anti-inflammatory capacity of Cu5.4O@CNDs. The therapeutic potential of Cu5.4O@CNDs was evaluated in vivo using mouse models of hepatic ischemia/reperfusion injury and LPS/D-GalN induced hepatitis, with transcriptome analysis conducted to clarify the mechanism underlying hepatoprotection. Results: The Cu5.4O@CNDs demonstrated superoxide dismutase (SOD) and catalase (CAT) enzyme activities, as well as hydroxyl radical (·OH) scavenging capabilities, effectively mitigating ROS in vitro. Furthermore, the Cu5.4O@CNDs exhibited remarkable targeting efficacy towards inflammation cells induced by H2O2 and hepatic tissues in murine models of hepatitis, alongside exhibiting favorable biocompatibility in both in vitro and in vivo settings. Moreover, it has been demonstrated that Cu5.4O@CNDs effectively scavenged ROS, thereby enhancing cell survival in vitro. Additionally, Cu5.4O@CNDs exhibited significant therapeutic efficacy in mice models of HIRI and lipopolysaccharide-induced acute lung injury (LPS-ALI). This efficacy was achieved through the modulation of the ROS response and hepatic inflammatory network, as well as the amelioration of disruptions in hepatic retinol metabolism. Conclusions: In summary, this study demonstrates that Cu5.4O@CNDs exhibit significant potential for the treatment of various acute liver injury conditions, suggesting their promise as an intervention strategy for clinical application.
Development of a robust BH3 drug toolkit for precision medicine in hematologic malignancies
Authors: Valentin Jacquier, Andréa Romero, Caroline Molinaro, Ritu Somayaji, Matthieu Abouladze, Ouissem Karmous Gadacha, Sara Ovejero, Hugues de Boussac, Ludovic Gabellier, Matthew S Davids, Jérôme Moreaux, Charles Herbaux
Journal: Theranostics (2025)

Rationale: In the era of precision medicine, there is a growing need for rapid reliable ex vivo functional assays capable of predicting treatment efficacy. One drug class that may particularly benefit from such assays is BH3 mimetics. These small molecules antagonize anti-apoptotic proteins such as BCL-2, MCL-1, or BCL-XL, on which cancer cells depend for their survival. A functional assay known as BH3 profiling was previously developed to measure those dependencies through the use of specific BH3-only peptides. A variation of this technique, dynamic BH3 profiling (DBP), allows for measuring changes in those dependencies, after ex vivo treatment with a drug of interest. Though well-validated to predict clinical response in hematologic malignancies, BH3 profiling technique requires the use of specialized BH3-only peptides and requires significant optimization to achieve reproducible results. Methods: We used a toolkit of BH3 mimetics drugs as probes instead of BH3-only peptides. This technique reduces the complexity and cost by using Annexin V/7AAD staining instead of cytochrome c release as a functional readout for apoptosis. We also used cell lines as internal controls for a representative response to BH3 mimetics that allow us to easily compare and stratify patients according to their profile. Results: We demonstrate that our new protocol enables apoptotic dependencies to be measured efficiently across different hematologic malignancies. In addition to a detailed description of the assay, we describe the results in several models including cell lines and primary tumor cells, both at baseline and dynamically after ex vivo drug treatments. We also compared BH3 toolkit baseline results on cell lines with those obtained using conventional BH3 profiling. Conclusion: Overall, our data validates this streamlined BH3 drug toolkit, allowing for a more extensive use of the BH3 profiling technique.
Bispecific Siglec-15/T cell antibody (STAB) activates T cells and suppresses pancreatic ductal adenocarcinoma and non-small cell lung tumors <i>in vivo</i>
Authors: Limei Shen, Alison Schaefer, Justin Huckaby, Whitney Wolf, Samuel K Lai
Journal: Theranostics (2025)

Rationale: Siglec-15 (S15) is a membrane-associated antigen overexpressed across various cancer types, and also induces immunosuppression. We believe this makes S15 a promising target for cellular immunotherapy of solid tumors characterized by an immunosuppressive tumor microenvironment, but this remains underexplored to date. Method: We engineered a bispecific antibody that simultaneously binds S15 on tumor cells and CD3 on T cells in the popular IgG-scFv format; we termed this molecule STAB. Results: In vitro, STAB induced marked proliferation of CD3+ T cells in human PBMCs, and mediated effective killing of Panc-1 pancreatic ductal adenocarcinoma (PDAC) and H460 non-small cell lung cancer (NSCLC) cells in co-culture studies with PBMCs or CD3+ T cells. In NSG mice with human PDAC and NSCLC tumors, STAB effectively suppressed tumor growth and prolonged survival, in sharp contrast to mice receiving either anti-S15 or anti-CD3 mAbs alone. STAB increased activated T cells in both tumor and circulation, as well as reduced the stromal barrier-a key hallmark of PDAC. Conclusion: Our results underscore STAb as a promising therapeutic molecule to be investigated further for PDAC and NSCLC, and potentially other S15-positive solid tumors.