tbuckley/cabot-search huggingface dataset:
Nano drug delivery systems for advanced immune checkpoint blockade therapy
Authors: Chenqi Guo, Ling Lin, Yihan Wang, Jing Jing, Qiyong Gong, Kui Luo
Journal: Theranostics (2025)

Immune checkpoint inhibitors (ICIs) have been widely utilized in the first-line therapy of various types of cancer. However, immune-related adverse events (irAEs) and resistance to ICIs remain intractable challenges for immune checkpoint blockade (ICB) therapy during clinic treatment. Nano drug delivery systems (NDDSs) have shown promising potential to improve anticancer efficacy and reduce side effects of small molecular drugs. The combination of nanotechnology and ICB provides new opportunities to overcome the challenges of immunotherapy. Nanoplatforms have been employed for direct delivery of ICIs, and they are preferred vehicles for combination therapy of ICIs and other therapeutic agents. In this review, the strategies of using NDDSs for advancing ICB therapy in recent years are surveyed, emphasizing the employment of NDDSs for combination treatment by ICIs and other agents to manipulate antitumor immunity. Analysis of current strategies for applying NDDSs for ICB leads to future research directions and development trends.
Optimizing theranostics chatbots with context-augmented large language models
Authors: Pia Koller, Christoph Clement, Albert van Eijk, Robert Seifert, Jingjing Zhang, George Prenosil, Mike M Sathekge, Ken Herrmann, Richard Baum, Wolfgang A Weber, Axel Rominger, Kuangyu Shi
Journal: Theranostics (2025)

Introduction: Nuclear medicine theranostics is rapidly emerging, as an interdisciplinary therapy option with multi-dimensional considerations. Healthcare Professionals do not have the time to do in depth research on every therapy option. Personalized Chatbots might help to educate them. Chatbots using Large Language Models (LLMs), such as ChatGPT, are gaining interest addressing these challenges. However, chatbot performances often fall short in specific domains, which is critical in healthcare applications. Methods: This study develops a framework to examine the use of contextual augmentation to improve the performance of medical theranostic chatbots to create the first theranostic chatbot. Contextual augmentation involves providing additional relevant information to LLMs to improve their responses. We evaluate five state-of-the-art LLMs on questions translated into English and German. We compare answers generated with and without contextual augmentation, where the LLMs access pre-selected research papers via Retrieval Augmented Generation (RAG). We are using two RAG techniques: Naïve RAG and Advanced RAG. Results: A user study and LLM-based evaluation assess answer quality across different metrics. Results show that Advanced RAG techniques considerably enhance LLM performance. Among the models, the best-performing variants are CLAUDE 3 OPUS and GPT-4O. These models consistently achieve the highest scores, indicating robust integration and utilization of contextual information. The most notable improvements between Naive RAG and Advanced RAG are observed in the GEMINI 1.5 and COMMAND R+ variants. Conclusion: This study demonstrates that contextual augmentation addresses the complexities inherent in theranostics. Despite promising results, key limitations include the biased selection of questions focusing primarily on PRRT, the need for comprehensive context documents. Future research should include a broader range of theranostics questions, explore additional RAG methods and aim to compare human and LLM evaluations more directly to enhance LLM performance further.
Nitric oxide-primed engineered extracellular vesicles restore bioenergetics in acute kidney injury via mitochondrial transfer
Authors: Fei Peng, Xiaoniao Chen, Lingling Wu, Jiayi He, Zongjin Li, Quan Hong, Qiang Zhao, Meng Qian, Xu Wang, Wanjun Shen, Tingting Qi, Yiyu Huang, Guangyan Cai, Chuyue Zhang, Xiangmei Chen
Journal: Theranostics (2025)

Background: The disruption of mitochondrial homeostasis in acute kidney injury (AKI) is an important factor that drives persistent renal dysfunction. Mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) have shown great therapeutic potential in AKI, but insufficient specificity of targeting the impaired mitochondrial function. Herein, we developed an engineered nitric oxide (NO)-primed MSC-EVs (pEVs) to restore mitochondrial homeostasis for AKI therapy. Methods: A cisplatin-induced AKI model was established to investigate the therapeutic effects of MSC-EVs. Proteomic and Western blot analyses compared mitochondrial cargos and functional assays included mitochondrial complex I activity and Adenosine triphosphate (ATP) quantification. Mitochondrial transfer was tracked using flow cytometry and confocal imaging. Mitochondrial dynamics, oxidative stress, and apoptosis were evaluated through ATP measurement, western blotting and rotenone-mediated respiratory chain inhibition. Results: Our data indicated that pEVs outperformed cEVs in restoring renal function and histopathology. Additionally, a reduction in mitochondria-associated oxidative stress and cell death was observed. Proteomic profiling revealed that NO priming enriched pEVs with mitochondrial complex I components, which directly enhanced their bioenergetic capacity, as evidenced by higher mitochondrial complex I activity and elevated ATP production compared to cEVs. In vivo tracking confirmed targeted delivery of pEV-derived mitochondrial contents to renal tubular cells, reducing mitochondrial reactive oxygen species (ROS) and restoring mitochondrial mass. Crucially, mitochondria-depleted pEVs abolished these therapeutic effects, establishing mitochondrial cargos as the primary therapeutic driver. Furthermore, pEVs activated a pro-survival cascade in recipient cells, showing superior efficacy in promoting mitochondrial biogenesis, dynamics, and mitophagy, thereby restoring renal mitochondrial homeostasis. Conclusion: Our study elucidated a mitochondria-targeted therapeutic strategy enabled by engineered EVs that deliver functional cargo to restore mitochondrial homeostasis. These advances provide transformative potential for AKI and other mitochondrial disorders.
Topoisomerase IIα-mediated stemness response in reactive astrocytes to traumatic brain injury
Authors: Shangyao Qin, Xiao Huang, Yimin Yuan, Hong Liu, Jiali Li, Ziwei Dai, Zhida Lan, Yingyan Pu, Cheng He, Zhida Su
Journal: Theranostics (2025)

Rationale: As a highly plastic population, parenchymal astrocytes have demonstrated the capacity to become activated and recapitulate neurogenic potential in response to traumatic central nervous system (CNS) injuries, representing a latent reservoir for neuronal regeneration in non-neurogenic brain regions. However, the extrinsic and intrinsic factors regulating this process remain poorly characterized. Elucidating these molecular mechanisms is crucial to harnessing the regenerative potential of reactive astrocytes in CNS repair. Methods: A multidisciplinary approach combining immunostaining, western blotting, RNA interference (RNAi), gene knock out and fate-mapping was used to investigate the role of topoisomerase IIα (TOP2a) in regulation of the stemness response in reactive astrocytes to traumatic brain injury (TBI). Results: Both in vitro and in vivo analyses demonstrated that TBI induces a stem cell-like response in reactive astrocytes concomitant with TOP2a upregulation. Pharmacological inhibition or genetic deletion of TOP2a significantly attenuated this stemness response. Neurosphere culture assay indicates that TOP2a might act as a downstream factor of Sonic Hedgehog (SHH) signaling to mediate the acquisition of stem cell potential. Conclusions: This study identifies TOP2a as a pivotal intrinsic regulator of astrocytic stem cell potential in the injured brain, which will advance our understanding of the molecular underpinnings of the stem cell response and its therapeutic application in neural regeneration.
Magnetic sculpture-like tumor cell vaccines enable targeted <i>in situ</i> immune activation and potent antitumor effects
Authors: Heng Zhang, Qing-Qing Li, Yue Shi, Lei Zhang, Kai-Wen Wang, Ting Wu, Shan-Bin Cheng, Zi-Ren Zhang, Lu-Ning Qin, Yun-Long Zhao, Xue-Ting Zhen, Hao-Ran Ren, Lin-Yong Du, Hui-Juan Liu, Tao Sun
Journal: Theranostics (2025)

Rationale: Tumor cells are ideal candidates for developing cancer vaccines due to their antigenic profiles, yet existing whole-cell vaccines lack efficacy. This study aimed to develop a novel whole-cell vaccine platform that combines immunogenicity, structural integrity, and tumor-targeting capabilities. Methods: We created "Magnetic Sculpture-like (MASK) Cells" by treating tumor cells with high-concentration FeCl3, inducing rapid morphological fixation without traditional chemical crosslinking. MASK cells were characterized for proliferative capacity, biomolecule retention, and magnetic properties. Vaccine efficacy was tested in vitro, in melanoma-bearing mouse models, and through spatial transcriptomic profiling of tumor microenvironments. Combination therapy with anti-PD-1 was further evaluated. Results: MASK cells lose proliferative ability but retain biomolecules and architecture. MASK cells promote dendritic cell maturation and T cell responses against tumors. Vaccines combining MASK cells and adjuvant potently suppress melanoma growth. Uniquely, FeCl3 sculpting imparts magnetism to cells, enabling directional navigation to tumors using magnetic fields and enhanced in situ immune activation. Spatial transcriptomics reveals DC and T cell activation and tumor cytotoxicity after MASK vaccination. Combined with anti-PD-1, MASK cell vaccines strongly inhibit growth and improve survival. Conclusion: MASK cells represent a promising new approach for targeted, patient-specific anti-tumor therapeutics.
Fish-derived biomaterials for tissue engineering: advances in scaffold fabrication and applications in regenerative medicine and cancer therapy
Authors: Seoyul Jo, Hanjun Hwangbo, Nacionales Francis, JaeYoon Lee, Mohan Pei, GeunHyung Kim
Journal: Theranostics (2025)

Fish-derived biomaterials, such as collagen, polyunsaturated fatty acids, and antimicrobial peptides, have emerged as promising candidates for scaffold development in stem cell therapies and tissue engineering due to their excellent biocompatibility and low immunogenicity. Although good bioactivity is a prerequisite for biomedical substitutes, scaffold design is necessary for the successful development of bioconstructs used in tissue regeneration. However, the limited processability of fish biomaterials poses a substantial challenge to the development of diverse scaffold structures. In this review, unlike previous reviews that primarily focused on the bioactivities of fish-derived components, we placed greater emphasis on scaffold fabrication and its applications in tissue regeneration. Specifically, we examined various cross-linking strategies to enhance the structural integrity of fish biomaterials and address challenges, such as poor processability, low mechanical strength, and rapid degradation. Furthermore, we demonstrated the potential of fish scaffolds in stem cell therapies, particularly their capacity to support stem cell growth and modulate the cellular microenvironment. Finally, this review provides future directions for the application of these scaffolds in cancer therapy.
Inorganic and hybrid nanomaterials for NIR-II fluorescence imaging-guided therapy of Glioblastoma and perspectives
Authors: Zhigang Li, Lixin Du, Binghua Du, Zia Ullah, Yinghe Zhang, Yanyang Tu, Ying Zhou, Bing Guo
Journal: Theranostics (2025)

Glioblastoma (GBM) is the most invasive and lethal brain tumor, with limited therapeutic options due to its highly infiltrative nature, resistance to conventional therapies, and blood-brain barriers. Recent advancements in near-infrared II (NIR-II) fluorescence imaging have facilitated greater tissue penetration, improved resolution, and real-time visualization of GBM, providing a promising approach for precise diagnosis and treatment. The inorganic and hybrid NIR-II fluorescent materials have developed rapidly for NIR-II fluorescence imaging-guided diagnosis and therapy of many diseases, including GBM. Herein, we offer a timely update to explore the contribution of inorganic/hybrid NIR-II fluorescent nanomaterials, such as quantum dots, rare-earth-doped nanoparticles, carbon-based nanomaterials, and metal nanoclusters in imaging-guided treatment for GBM. These nanomaterials provide high photostability, strong fluorescence intensity, and tunable optical properties, allowing for multimodal imaging and enhanced therapeutic efficacy. Additionally, their integration with modern therapeutic strategies, such as photothermal therapy, chemodynamic therapy, photodynamic therapy, sonodynamic therapy, and immunotherapy, has shown significant potential in overcoming the limitations of traditional treatments. Looking forward, future advancements including safe body clearance, long-term biocompatibility, efficient BBB penetration, and extended emission wavelengths beyond 1500 nm could enhance the theranostic outcomes. The integration of dual imaging with immunotherapy and AI-driven strategies will further enhance precision and accelerate the clinical translation of smart theranostic platforms for GBM treatment.
Shh agonist enhances maturation in homotypic Lgr5-positive inner ear organoids
Authors: Nathaniel T Carpena, So-Young Chang, Seyoung Mun, Kyung Wook Kim, Hyun C Yoon, Phil-Sang Chung, Ji-Hun Mo, Jin-Chul Ahn, Ji On Park, Kyudong Han, Ji Eun Choi, Jae Yun Jung, Min Young Lee
Journal: Theranostics (2025)

Background: The regeneration of functional hair cells (HCs) remains a critical challenge in addressing sensorineural hearing loss. This study aimed to investigate the molecular and functional mechanisms driving stereocilia maturation within inner ear organoids (IEO) derived from homogenic Lgr5-positive progenitor cells (LPCs) and to compare outcomes with traditional heterotypic cultures. Methods: Mouse cochlear LPCs were isolated via magnetic-activated cell sorting (MACS) to establish homotypic cultures, ensuring purity and eliminating the heterotypic influences present in traditional manual isolation (MI) methods. Differentiation into HCs was induced through Wnt and Notch signaling modulation. Transcriptomic profiling using bulk and single-cell RNA sequencing (scRNA-seq) identified gene expression changes linked to stereocilia development. A Sonic Hedgehog (Shh) agonist was applied to enhance structural maturation of HCs. Functional assessment included electron microscopy, FM1-43 uptake assays, and microelectrode array recordings in assembloids of IEO with primary spiral ganglion neurons (SGN) co-cultures. Results: While homotypic LPC-derived IEOs successfully differentiated into HC-like cells, initial morphological assessment revealed immature stereocilia structures. Bulk RNA-seq analysis highlighted a downregulation of morphogenesis-related genes in these organoids. The application of a Shh agonist, acting as a key morphogen, promoted stereocilia development, as evidenced by enhanced ultrastructural features and increased expression of cuticular plate-associated genes (Pls1, Lmo7 and Lrba). Single-cell RNA sequencing (scRNA-seq) further identified distinct cell clusters, which exhibited robust expression of stereocilia-related genes (Espn, Lhfpl5, Loxhd1 and Tmc1), indicative of advanced HC maturation. Electrophysiological assessments of IEO-SGN assembloids using microelectrode arrays confirmed functional mechanoelectrical transduction between cells. Conclusion: This integrated approach elucidates critical pathways and cellular dynamics underpinning stereocilia maturation and functional HC development in EIOs. These findings provide new insights into the molecular regulation of HC maturation and support the utility of Shh-modulated IEOs as a promising platform for inner ear regeneration and therapeutic development for inner ear regenerative therapies.
Single-nucleus RNA sequencing and spatial transcriptomics reveal an immunosuppressive tumor microenvironment related to metastatic dissemination during pancreatic cancer liver metastasis
Authors: Hongsen Liu, Mengting Chen, Bo Hong, Yufei Xiao, Qianming Chen, Yun Qian
Journal: Theranostics (2025)

Background: Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive malignancy characterized by early liver metastasis and high mortality. The tumor microenvironment plays a pivotal role in tumor progression; however, the immune microenvironment's involvement in PDAC liver metastasis remains poorly understood. Methods: This study investigates cellular heterogeneity in primary tumor (PT) and liver metastasis (LM) tissues of PDAC using single-nucleus RNA sequencing and spatial transcriptomics. Intra-tumor heterogeneity and cell interactions were elucidated through deconvolution, intercellular signalling, pseudotime analysis, and immune infiltration profiling. The spatial distribution of immune cells was assessed by multiplexed immunofluorescence staining, and prognostic models were developed and validated through immunohistochemistry (IHC). Analyzing the regulatory role of CITED4 in the invasion and metastasis of pancreatic cancer cells through transwell assay and scratch wound healing assay. Results: A total of 62,326 cells were sequenced, with metastatic dissemination cells showing significant upregulation of epithelial-mesenchymal transition (EMT)-related genes during liver metastasis. Spatial transcriptomics revealed the enrichment of metastatic dissemination cells and FOXP3-related Treg cells at the tumor front in PT tissues. In comparison to LM tissues, the tumor front in PT tissues fosters an immunosuppressive microenvironment through the accumulation of Treg cells. Interaction analysis identified the SPP1 pathway as a key promoter of this immunosuppressive environment. Furthermore, prognostic models highlighted CITED4 as critical biomarkers in PDAC. Elevated CITED4 expression is correlated with liver metastasis and poor prognosis in patients with PDAC. siRNA-mediated knockdown of CITED4 suppresses the invasion and metastasis of pancreatic cancer cells. Conclusions: In summary, this study revealed that Treg cell alterations, mediated by metastatic dissemination cells within the immune microenvironment, significantly contribute to PDAC liver metastasis, and that CITED4 enhances the metastatic potential of metastatic dissemination cells.
Targeting endothelial MYC using siRNA or miR-218 nanoparticles sensitizes chemo- and immuno-therapies by recapitulating the Notch activation-induced tumor vessel normalization
Authors: Xianchun Yan, Ziyan Yang, Xiuli Cao, Liang Liang, Yanyan Duan, Peiran Zhang, Yixuan Feng, Ting Wen, Shanqiang Luo, Lintao Jia, Jiaxing Sun, Hua Han
Journal: Theranostics (2025)

Background: The chaotic, over-activated tumor vasculature promotes tumor growth and erodes most current therapies. Although Notch activation critically regulates angiogenesis, the broad roles of Notch has dampened its druggability. Methods: Gene-modified mice with a Cdh5-CreERT transgene were employed to activate/block Notch signaling in endothelial cells (ECs). Multiple transcriptome analyses were conducted to compare gene expression profiles. qRT-PCR and western blotting were used to determine gene expression level. Immunofluorescence and flow cytometry were used to observe morphological alterations and immune microenvironment in tumors. Nanoparticles (PEI-PEG-cRGD) were used to deliver siRNA into tumor ECs (TECs) in vivo. Results: Genetic Notch activation or blockade in TECs normalizes or deteriorates tumor vessels, respectively. Single-cell RNA sequencing showed that Notch activation selectively reduced the proliferating TEC subset, which accounted for about 30% of TECs and gave rise to other TEC subsets. Notch activation or blockade downregulated or upregulated MYC, respectively. MYC overexpression canceled Notch activation-induced proliferation arrest of TECs in vitro, and a MYC inhibitor normalized tumor vessels in RBPj deficient mice, suggesting that MYC is the authentic Notch target in normalizing tumor vessels. Nanoparticles encapsulated with MYC siRNA (EC-siMYC) or miR-218 (EC-miR-218), a Notch-downstream miRNA suppressing MYC, were able to mitigate Notch inhibition-induced tumor vessel defects. Combination of cisplatin with MYC blockade exhibited improved therapeutic effects. Moreover, MYC blockade promoted T cell infiltration and enhanced anti-PD1 immunotherapy. Conclusions: Together, our data have demonstrated that Notch activation normalizes tumor vessels by repressing the proliferating TEC subset via MYC, and targeting endothelial MYC using nanoparticles bearing siRNA or miRNA is an efficient strategy for tumor anti-angiogenic therapy.
BARD1-mediated stabilization of METTL14 promotes retinal neovascularization by m6A-modifying MXD1 mRNA on a YTHDF2-dependent manner
Authors: Xianyang Liu, Shuhao Zeng, Jiayu Meng, Qian Zhou, Fan Cao, Baorui Chu, Chao Wu, Yakun Wang, Hui Feng, Xiaorui Bi, Xinyuan Chen, Wenxian Yang, Meng Tian, Hui Yang, Ke Hu, Shengping Hou
Journal: Theranostics (2025)

Retinal vascular diseases are typified by the proliferation of irregular and leaky microvessels, resulting in vision impairment. Although the etiology of retinal angiogenesis is not yet fully understood, it is evident that microglia play a pivotal role in promoting angiogenesis. Methods: In vivo, the METTL14 conditional knockout (cKO) mouse was constructed to investigate the role of METTL14 in oxygen-induced retinopathy (OIR). In vitro, a combination of methylated RNA immunoprecipitation sequencing (MeRIP-seq), RNA-sequencing (RNA-seq), RNA Immunoprecipitation (RIP) assay, dual-luciferase reporter assays, and Chromatin immunoprecipitation-qPCR (ChIP-qPCR), was performed to explore the underlying mechanisms. Results: The proteomic analysis of hypoxic microglia has uncovered a pronounced enrichment in pathways related to RNA modification. Western blot has revealed that N6-methyladenosine (m6A) methyltransferase-like 14 (METTL14) exhibits the most significant increase among the RNA methylases. METTL14 cKO mice within an OIR model showed fewer neovascular formations. Additionally, in co-culture with sh-METTL14 HMC3 cells, HRMECs also exhibited reduced angiogenesis capabilities. Mechanically, E3 ubiquitin-protein ligase BARD1 can directly interact with METTL14, leading to an up-regulation of METTL14 protein level in hypoxic microglia. METTL14 could directly modifies and regulates the transcription factor MAX Dimerization Protein 1 (MXD1), which is subsequently recognized by the m6A "reader" YTH domain-containing family protein 2 (YTHDF2). Consequently, the modified MXD1 modulates the expression of VEGFA and VCAM1, promotes retinal neovascularization. Conclusion: Our study highlights the critical role of METTL14 in the OIR model and suggests a novel therapeutic target for addressing retinal vascular diseases.