Theranostics最新文献

{"title":"Ultrasound flow imaging for assessing cerebrovascular changes following focused-ultrasound blood-brain barrier opening.","authors":"Sua Bae, Stephen A Lee, Seongyeon Kim, Fotios Tsitsos, Yangpei Liu, Elisa E Konofagou","doi":"10.7150/thno.98098","DOIUrl":"10.7150/thno.98098","url":null,"abstract":"<p><p><b>Rationale</b>: Microbubble-mediated focused ultrasound (Mb-FUS) is a promising non-invasive technique for blood-brain barrier opening (BBBO), enhancing drug delivery and immunomodulation for brain disease treatments. In Mb-FUS, microbubble cavitation exerts mechanical stress on blood vessel walls. While cavitation is commonly used for monitoring, leveraging the vascular response to predict treatment outcomes remains unexplored. This study pioneers the use of ultrasound flow imaging with microbubbles to investigate the cerebrovascular changes induced by Mb-FUS and assesses the feasibility of this imaging technique for predicting BBBO treatment outcomes. <b>Methods</b>: We utilized contrast-enhanced power Doppler (CEPD) and ultrasound localization microscopy (ULM) to monitor and quantify Mb-FUS-induced cerebrovascular changes in mice (n=4 without skull, n=12 with skull). The left hippocampus/thalamus regions were targeted for Mb-FUS BBBO. Pre- and post-FUS images were acquired, with continuous monitoring of CEPD intensity to ensure consistency in microbubble concentration. We observed changes in the number of microbubbles detected, their speeds, and vessel diameter after Mb-FUS. <b>Results</b>: Reductions in blood volume, vessel diameter, and flow speed were observed in the sonicated regions. We demonstrated the transcranial capability of CEPD and ULM to detect Mb-FUS-induced vascular changes by observing linear relationships between the reductions in blood volume and flow, and the size of the opening or edema. Furthermore, local signal reduction detected by transcranial CEPD map spatially co-localized with the edema region identified in T2-weighted MRI. <b>Conclusion</b>: We have developed a method to quantify changes in blood volume, flow speed, and vessel diameter following Mb-FUS using ultrasound flow imaging (CEPD and ULM) with microbubbles. For the first time, the blood vessels post-FUS were assessed by ultrasound flow imaging that visualizes associated vascular changes and potential damage. This technique not only holds potential for predicting treatment outcomes but also paves the way for a unified ultrasound-based system for both treatment and monitoring, with potential for future clinical translation.</p>","PeriodicalId":22932,"journal":{"name":"Theranostics","volume":"15 18","pages":"10028-10044"},"PeriodicalIF":13.3,"publicationDate":"2025-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12486155/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145213713","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Deep brain stimulation-induced normalization of hippocampal synchrony in a transgenic rat model of Alzheimer's disease.","authors":"Andrea Trevisiol, Tina Beckett, Monica Bell Vila, Mary Hill, Joanne McLaurin, Bojana Stefanovic","doi":"10.7150/thno.110292","DOIUrl":"10.7150/thno.110292","url":null,"abstract":"<p><p><b>Background and Aim:</b> Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by disrupted neural network dynamics and neuronal loss. Deep brain stimulation (DBS) may restore network function and abate cognitive deficits. In a transgenic rat model of AD, we investigated the dependence of hippocampal neuronal activity on a range of DBS parameters, aiming to identify stimulation conditions that transiently restore impaired network function. <b>Material and Methods:</b> We used 16-month-old TgF344-AD and NTg rats under light anesthesia and performed simultaneous DBS and high-resolution intracerebral recordings in the hippocampus using a linear multielectrode array. DBS was delivered in bipolar mode, at varying frequencies, amplitudes and duration, while monitoring local field potentials (LFP) and spiking activity. Phase-amplitude coupling (PAC), neuronal power, and firing rates were analyzed prior to and following DBS. Linear mixed effects models were used to evaluate the influence of genotype, sex, and stimulation parameters on the electrophysiological markers. <b>Results:</b> With increasing DBS frequency and amplitude, hippocampal power and PAC rose in all rats, particularly within the delta-theta range. When compared to NTgs, TgAD rats showed attenuated power but increased PAC responses to DBS. Low frequency DBS induced higher entrainment in the post- relative to during-DBS period in all animals. Compared to their non-transgenic littermates, TgAD rats showed reduced entrainment responses. <b>Conclusions:</b> These findings demonstrate that hippocampal responses to DBS have a parameter-dependent profile that is differentially modulated by AD pathology. Our study provides a foundation for tailoring DBS parameters to compensate for distinct neuronal deficits in established AD, supporting the use of electrophysiological biomarkers to guide individualized neuromodulation strategies.</p>","PeriodicalId":22932,"journal":{"name":"Theranostics","volume":"15 18","pages":"10064-10075"},"PeriodicalIF":13.3,"publicationDate":"2025-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12486142/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145213610","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"MR molecular imaging for monitoring and predicting tumor responses to immunotherapy.","authors":"Victoria E A Laney, Walter Zhao, Inga M Hwang, Emma Hampson, Juan Dong, Ryan C Hall, Kristin Weber-Bonk, Xueer Yuan, Elizabeth Delaney, Hannah Gilmore, Ruth Keri, Jordan Winter, Li Lily Wang, Zheng-Rong Lu","doi":"10.7150/thno.106481","DOIUrl":"10.7150/thno.106481","url":null,"abstract":"&lt;p&gt;&lt;p&gt;&lt;b&gt;Background:&lt;/b&gt; While immunotherapies show great promise in cancer treatment, variability in patient responses warrant the need for improved methods to assess early responses and guide precision therapy. The tumor microenvironment (TME) plays a critical role in antitumor immunity and tumor response to immunotherapy. Critically, TME components and their crosstalk with immune cells can be leveraged as a prognostic marker for therapeutic response. This study evaluated the use of magnetic resonance molecular imaging (MRMI) targeting the TME protein extradomain B fibronectin (EDB-FN), which is a lymphokine secreted by activated T lymphocytes and a marker of the epithelial-to-mesenchymal transition (EMT) in aggressive tumor cells. MRMI of EDB-FN was evaluated within the tumor extracellular matrix and was correlated with immunotherapy-related outcomes. &lt;b&gt;Methods:&lt;/b&gt; C57BL/6 mice bearing orthotopic KPC pancreatic tumors were treated with a novel immune checkpoint inhibitor (VISTA-blocking antibodies), a vaccine (mutant KRAS&lt;sup&gt;G12D&lt;/sup&gt; peptide with TLR7/8/9 agonists), or a combination of both. MRMI with an EDB-FN-specific contrast agent, MT218, was used to image tumor responses during treatment. T&lt;sub&gt;1&lt;/sub&gt;-weighted MRI (fast spin echo and FLASH sequences) was acquired before, during, and after tumor treatment. Tumor signal enhancement patterns were analyzed to assess treatment response. EDB-FN expression and the infiltration of CD4&lt;sup&gt;+&lt;/sup&gt; and CD8&lt;sup&gt;+&lt;/sup&gt; T lymphocytes in the tumors were determined by immunohistochemistry (IHC) and immunofluorescence (IF) staining, respectively, and correlated with MRMI observations, tumor response, and therapeutic outcomes. &lt;b&gt;Results:&lt;/b&gt; MT218-MRMI revealed distinctive signal enhancement patterns across different treatments. These patterns were detected as early as two weeks after treatment initiation and correlated strongly with EDB-FN expression and CD4&lt;sup&gt;+&lt;/sup&gt; and CD8&lt;sup&gt;+&lt;/sup&gt; T cell infiltration, as confirmed by IHC and IF. Signal profiles corresponded to known TME phenotypes: immune desert, immune excluded, and immune inflamed, which were associated with non-response, partial response, and complete response, respectively. By four weeks post-treatment, MRMI criteria successfully distinguished complete responders from partial responders. Over a 200-day monitoring period, outcome prediction showed complete (100%) long-term disease-free survival in complete responders, 24-27% survival in partial responders, and no (0%) survival in non-responders and those with stable disease. &lt;b&gt;Conclusion:&lt;/b&gt; MT218-MRMI non-invasively distinguishes tumor response patterns with significant potential for early prediction of therapeutic outcomes and timely optimization of treatment strategies. While further validation is needed for clinical translation, these findings demonstrate MT218-MRMI's promise as a tool for monitoring immunotherapy response in pancreatic cancer and underscore its potential utilit","PeriodicalId":22932,"journal":{"name":"Theranostics","volume":"15 18","pages":"10045-10063"},"PeriodicalIF":13.3,"publicationDate":"2025-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12486160/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145213649","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Bone remodeling stimulated by Wnt-mediated mitophagy regulated extracellular vesicles in subchondral bone contributes to osteoarthritis development.","authors":"Yuyuan Gu, Qirong Zhou, Shihao Sheng, Huijian Yang, Dan Huang, Qin Zhang, Hao Zhang, Zijian Cao, Yuanwei Zhang, Zuhao Li, Yingying Jiang, Xiao Chen, Yingying Jing, Chenglong Wang, Hongbo Tan, Ke Xu, Jiacan Su","doi":"10.7150/thno.111724","DOIUrl":"10.7150/thno.111724","url":null,"abstract":"<p><p><b>Rationale:</b> Osteoarthritis (OA) is increasingly understood as a disease involving not only cartilage degeneration but also pathological subchondral bone remodeling. The contribution of osteoblast (OB) heterogeneity and their secreted extracellular vesicles (EVs) to this process remains poorly characterized. This study aims to investigate how EVs from distinct OB subtypes modulate subchondral bone remodeling and contribute to OA progression. <b>Methods:</b> OB subtypes representing endothelial (EnOBs), stromal (StOBs), and mineralizing (MinOBs) stages were generated by time-controlled osteogenic induction of BMSCs. EVs were isolated from each OB subtype and characterized by TEM, Western blot, DLS, and miRNA profiling. Functional assays included osteogenic induction, angiogenesis, and cartilage degradation analyses in vitro. RNA-seq and qRT-PCR were used to identify relevant signaling pathways and miRNAs. In vivo effects of EVs were tested in a DMM-induced OA mouse model using intravenous injections, followed by histology, micro-CT, and immunostaining. <b>Results:</b> EVs derived from different OB subtypes exhibited distinct pro-osteogenic, pro-angiogenic, and cartilage-degrading effects. MinOB-derived EVs significantly enhanced osteogenic differentiation and mineralization, correlated with enrichment of calcium phosphate content and specific pro-osteogenic miRNAs. These EVs also carried amorphous calcium phosphate and mitochondrial content, linked to activated mitophagy. Wnt signaling dynamically regulated mitophagy and EV composition, particularly in MinOBs. In vivo, tail vein administration of OB-derived EVs exacerbated subchondral bone sclerosis and cartilage degradation in a time-dependent manner, with MinOB-EVs inducing the most pronounced pathological changes. <b>Conclusions:</b> OB-derived EVs exhibit subtype-dependent regulatory functions in subchondral bone remodeling, mediated by distinct miRNA profiles and mineral cargo shaped by Wnt-regulated mitophagy. These EVs actively participate in OA progression, and their effects vary with disease stage and route of administration. Targeting specific OB subtypes or modulating Wnt-mitophagy signaling may offer novel therapeutic strategies for stage-specific OA intervention.</p>","PeriodicalId":22932,"journal":{"name":"Theranostics","volume":"15 18","pages":"10007-10027"},"PeriodicalIF":13.3,"publicationDate":"2025-09-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12486141/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145213652","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Erratum: An electroporation strategy to synthesize the membrane-coated nanoparticles for enhanced anti-inflammation therapy in bone infection: Erratum.","authors":"Miusi Shi, Kailun Shen, Bin Yang, Peng Zhang, Kangle Lv, Haoning Qi, Yunxiao Wang, Mei Li, Quan Yuan, Yufeng Zhang","doi":"10.7150/thno.121003","DOIUrl":"https://doi.org/10.7150/thno.121003","url":null,"abstract":"<p><p>[This corrects the article DOI: 10.7150/thno.48407.].</p>","PeriodicalId":22932,"journal":{"name":"Theranostics","volume":"15 17","pages":"9200"},"PeriodicalIF":13.3,"publicationDate":"2025-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12439465/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145081603","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Hsa_circ_0058495-mediated IGF2BP2 ubiquitination and m6A modification of MEKK1 promote the progression of PDAC.","authors":"Shengnan Lv, Jian Zhang, Xinyu Peng, Huan Liu, Tongjia Chu, Ziyu Liu, Kehang Duan, Jianxiong Guo, Jie Wang, Yan Liu, Feng Wei","doi":"10.7150/thno.117202","DOIUrl":"10.7150/thno.117202","url":null,"abstract":"<p><p><b>Background</b>: Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive malignancy with dismal clinical outcomes. We identified hsa_circ_0058495 as significantly upregulated in PDAC tissues and PDAC cell-derived exosomes, where it contributes to tumor proliferation and invasion. The molecular mechanisms underlying its oncogenic function, however, remain incompletely understood. <b>Methods:</b> Differential circRNA expression was profiled by RNA sequencing. The functional role of hsa_circ_0058495 and its molecular interactions were interrogated through Western blotting, RT-qPCR, co-immunoprecipitation, RNA pull-down, and RNA immunoprecipitation assays. Confocal microscopy and PET/CT imaging were employed to delineate its biological effects <i>in vitro</i> and <i>in vivo</i>. <b>Results:</b> Hsa_circ_0058495 was enriched in PDAC-derived exosomes and stabilized IGF2BP2 by preventing TRIM25-mediated ubiquitination and attenuating autophagy-dependent degradation. Stabilized IGF2BP2 enhanced the stability of MEKK1 mRNA, leading to sustained ERK1/2 phosphorylation and consequent promotion of PDAC cell proliferation and invasion. Moreover, exosomal hsa_circ_0058495 facilitated M2 macrophage polarization, thereby fostering an immunosuppressive tumor microenvironment. <b>Conclusions:</b> Hsa_circ_0058495 promotes PDAC progression by stabilizing IGF2BP2 and activating the MEKK1-ERK signaling cascade, while exosomal transfer of hsa_circ_0058495 drives M2 macrophage polarization to reinforce tumor-associated immunosuppression. These findings establish hsa_circ_0058495 as a pivotal regulator of PDAC progression and underscore its potential utility as both a diagnostic biomarker and a therapeutic target.</p>","PeriodicalId":22932,"journal":{"name":"Theranostics","volume":"15 18","pages":"9922-9943"},"PeriodicalIF":13.3,"publicationDate":"2025-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12486403/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145213706","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"GM-CSF⁺ Th: a central player in autoimmunity.","authors":"Sha-Sha Fan, Xuan Xu, Yu-Bin Luo, Xiang-Yu Meng, Yi Liu","doi":"10.7150/thno.121766","DOIUrl":"10.7150/thno.121766","url":null,"abstract":"<p><p>Autoimmune diseases are driven by a breach of self-tolerance, leading to chronic inflammation and organ damage. While the Th1 and Th17 paradigms have long dominated our understanding of T-cell-mediated pathology, a distinct subset of CD4⁺ T helper cells defined by the production of granulocyte-macrophage colony-stimulating factor (GM-CSF) has emerged as a central and non-redundant pathogenic driver. These GM-CSF-producing Th cells orchestrate autoimmune pathology across a spectrum of diseases, including multiple sclerosis, rheumatoid arthritis, and type 1 diabetes, among others. Mechanistically, they act as critical amplifiers of inflammation by activating and recruiting myeloid cells, which in turn mediate tissue destruction. Furthermore, they establish vicious feedback loops, enhancing their own differentiation and promoting the function of other effector T cells. Despite their established importance, significant heterogeneity and plasticity exist in their phenotype and regulatory networks, with context-dependent variations across different diseases and species. This review synthesizes our current understanding of these pivotal cells, critically evaluating their classification, molecular identity, and the signaling pathways governing their differentiation. We further dissect their specific roles in major autoimmune diseases and provide a forward-looking perspective on their immense translational potential, from novel therapeutic strategies targeting the GM-CSF axis to their use as biomarkers for patient stratification and monitoring.</p>","PeriodicalId":22932,"journal":{"name":"Theranostics","volume":"15 18","pages":"9944-9968"},"PeriodicalIF":13.3,"publicationDate":"2025-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12486991/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145213682","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"ROS-targeting heterojunction-integrated GelMA microneedles for photo-responsive antioxidative action and accelerated diabetic wound healing.","authors":"Jinlan Tang, Weijun Liu, Zhengyao Zhang, Ye Yang, Wenwen Cheng, Xiaoyu Wang, Zesheng Chen, Zijian Wang, Weikang Hu","doi":"10.7150/thno.120879","DOIUrl":"10.7150/thno.120879","url":null,"abstract":"<p><p><b>Background:</b> Excessive oxidative stress activation in diabetic chronic wounds causes ongoing inflammation and cell dysfunction, which greatly impairs healing. Heterojunction photocatalytic nanozymes can potentially scavenge reactive oxygen species (ROS), but their clinical application faces challenges due to low photocatalytic efficiency, poor biocompatibility, and limited stability in physiological environments. <b>Methods:</b> APTES-COF-1@MXene heterojunction nanozymes (AC-1@MXene) were synthesized using chemical methods combined with in-situ growth techniques. Double-layered hydrogel microneedle systems (ACMGM) were fabricated through UV polymerization with tips loaded with AC-1@MXene. The photocatalytic performance of the nanozymes was assessed using physicochemical methods. Biocompatibility was confirmed through biochemical assays, and the therapeutic effectiveness of ACMGM was evaluated in diabetic mouse wound models. <b>Results:</b> AC-1@MXene multifunctional photocatalytic nanozymes were successfully developed, exhibiting both catalase and superoxide dismutase activities. These nanozymes demonstrated significantly enhanced enzymatic activity under visible light, efficiently converting H₂O₂ and ·O₂ ^- into H₂O and O₂, thus providing strong antioxidant protection. <i>In vitro</i> tests confirmed excellent biocompatibility, while <i>in vivo</i> studies showed that ACMGM microneedles effectively facilitated transdermal delivery of nanozymes. This significantly aided diabetic wound healing and reduced local oxidative stress. Mechanistic insights revealed that tissue regeneration and repair resulted from synergistic effects, including anti-inflammatory actions, M2 macrophage polarization, angiogenesis, and increased collagen synthesis. <b>Conclusion:</b> The ACMGM microneedle system effectively delivers nanozymes through the skin and enhances their catalytic activity upon exposure to visible light. This precisely modulates the oxidative stress microenvironment in refractory wounds, offering an innovative therapeutic strategy for diabetic wound treatment.</p>","PeriodicalId":22932,"journal":{"name":"Theranostics","volume":"15 18","pages":"9987-10006"},"PeriodicalIF":13.3,"publicationDate":"2025-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12486989/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145213585","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"EZH2-mediated H3K27me3 links microbial inosine loss to depression: a gut-brain epigenetic switch.","authors":"Sen Zhu, Xuan Li, Ying Yu, Xiaoyi Han, Fang Yang, Mengxi Lu, Gaole Dai, Liang Guo, Dan Xu","doi":"10.7150/thno.120824","DOIUrl":"10.7150/thno.120824","url":null,"abstract":"<p><p><b>Background:</b> Depression, the second most prevalent neurological disorder globally, affects over 300 million people and presents an urgent public health challenge. While gut microbiota dysbiosis is increasingly recognized as a key contributor to depression, the molecular mechanisms linking microbial imbalance to brain dysfunction remain poorly defined. <b>Methods:</b> We investigated the role of EZH2 in gut microbiota-induced depressive behaviors in mice using the chronic unpredictable mild stress (CUMS), fecal microbiota transplantation, and conditional knockout of EZH2. CUT&Tag sequencing was employed to analyze EZH2-mediated H3K27me3 epigenetic reprogramming. Untargeted metabolomics and luciferase reporter assays were used to identify metabolites that upregulate EZH2 expression. 16S rRNA sequencing combined with metabolic tracing was conducted to trace the microbial origin of inosine. Additionally, natural compound screening identified coumaric acid (CA) as a novel EZH2-targeting degrader. <b>Results:</b> Conditional knockout of neuronal <i>Ezh2</i> abolishes microbiota-induced depressive behaviors and neuronal apoptosis. Mechanistically, reduced abundance of specific microbiota (<i>f_Lachnospiraceae, f_Oscillospiraceae, and f_Erysipelotricaceae</i>) leads to inosine depletion. This depletion subsequently elevates EZH2 transcriptional activity by increasing H3K9ac modification at its locus, mediated through attenuation of the A2aR-cAMP-PKA-CREB-HDAC3 signaling axis. Subsequently, EZH2 silences serotonergic synapse-related genes (e.g., <i>Tph2, Htr2a, Htr6</i>) <i>via</i> H3K27me3 reprogramming, ultimately driving depressive behaviors and neuronal apoptosis in mice. Importantly, CA is identified as a first-in-class EZH2 degrader that binds lysine residues K623/K646 and recruits UBE3A for proteasomal degradation. CA treatment restores synaptic integrity and reverses depressive behaviors with minimal toxicity. <b>Conclusions:</b> Collectively, these findings define a novel \"microbiota-inosine-EZH2\" axis in depression pathogenesis and highlight EZH2 degradation as a promising therapeutic strategy for microbiota-associated neuropsychiatric disorders.</p>","PeriodicalId":22932,"journal":{"name":"Theranostics","volume":"15 18","pages":"9969-9986"},"PeriodicalIF":13.3,"publicationDate":"2025-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12486992/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145213760","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Chemo-RaST with bortezomib inhibits multiple myeloma relapse.","authors":"Anchal Ghai, Alexander Zheleznyak, Christopher Egbulefu, Nicole Blasi, Kvar Black, Rui Tang, Matthew L Cooper, Kiran Vij, Ravi Vij, John DiPersio, Monica Shokeen, Samuel Achilefu","doi":"10.7150/thno.111508","DOIUrl":"10.7150/thno.111508","url":null,"abstract":"<p><p><b>Rationale:</b> Multiple myeloma (MM) is a hematological malignancy with a high relapse rate that ultimately leads to patient mortality. Current therapies often fail to achieve sustained remission due to adaptation of clonally heterogeneous tumor populations. We hypothesized that Chemo-RaST, a therapeutic strategy combining bortezomib with ⁸⁹Zr-daratumumab-mediated radionuclide dynamic therapy (RaST), would synergize photophysical generation of cytotoxic reactive oxygen species (ROS) with mitochondrial ROS induction to block clonal adaptation and prevent MM relapse. <b>Methods:</b> We evaluated chemo-RaST in MM.1S-luc subcutaneous and disseminated MM mouse models. RaST consisted of zirconium-89 (⁸⁹Zr)-labeled daratumumab to target MM cells and continuously activate orthogonally delivered titanium dioxide-transferrin-titanocene (TiO₂-Tf-TC) nanoparticles for sustained cytotoxic ROS production. Bortezomib, a proteasome inhibitor, was administered in parallel to amplify mitochondrial ROS. Therapeutic efficacy was evaluated using bioluminescence imaging (BLI), positron emission tomography (PET), and histopathology. <b>Results:</b> <i>In vitro</i>, RaST reduced MM.1S-luc cell viability to 48.4 ± 2.0% versus untreated controls (98.7 ± 1.5%), TiO₂-Tf-TC nanoparticles alone (96.6 ± 0.8%), or ⁸⁹Zr-daratumumab alone (91.3 ± 3.4%). <i>In vivo</i>, RaST suppressed tumor progression, but relapse occurred. In contrast, chemo-RaST achieved complete tumor regression in 60% of disseminated MM models and significantly extended progression-free survival. Histopathology confirmed elimination of CD138-positive MM cells and restoration of normal hematopoiesis in Chemo-RaST cohorts. <b>Conclusions:</b> Tracer doses of long-lived ⁸⁹Zr for sustained photosensitizer activation, combined with subtherapeutic bortezomib, represent a clinically translatable strategy to limit off-target toxicity, prevent relapse, and overcome therapy resistance in multiple myeloma.</p>","PeriodicalId":22932,"journal":{"name":"Theranostics","volume":"15 18","pages":"9911-9921"},"PeriodicalIF":13.3,"publicationDate":"2025-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12486394/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145213665","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}