Theranostics最新文献

{"title":"Pretargeted ¹⁷⁷Lu/²²⁵Ac combination therapy of colorectal cancer.","authors":"Sara S Rinne, Niloufar Salehi, Brett A Vaughn, Daniela Burnes Vargas, Hongfen Guo, Sang Gyu Lee, Claire Vanpouille-Box, Ileana C Miranda, Brian W Miller, Edward K Fung, Steven M Larson, Darren R Veach, Nai-Kong V Cheung, Sarah M Cheal","doi":"10.7150/thno.126399","DOIUrl":"https://doi.org/10.7150/thno.126399","url":null,"abstract":"<p><strong>Rationale: </strong>Combining targeted alpha and beta therapy may address challenges such as toxicity, treatment resistance, and tumor heterogeneity. We evaluated the feasibility and therapeutic effectiveness of a DOTA-PRIT approach using a ¹⁷⁷Lu/²²⁵Ac radioisotope cocktail, directly compared with monotherapies targeting GPA33 in human colorectal cancer (CRC) xenografts in mice.</p><p><strong>Methods: </strong>A three-step pretargeting regimen was employed: an anti-GPA33/anti-DOTA bispecific antibody (BsAb), a dendrimeric clearing agent, and radioligands labeled with ¹⁷⁷Lu, ²²⁵Ac, alone or in combination. Serial biodistribution studies in GPA33(+) SW1222 xenografts evaluated how co-injection of ¹⁷⁷Lu and ²²⁵Ac radioligands affected tumor uptake and biodistribution. iQID digital autoradiography was used to visualize isotope distribution in tumor and kidney samples. Mice bearing SW1222 and LS174T xenografts received mono- or combination-therapy regimens delivering 37-38 Gy to tumors. Dose-escalation studies, histopathology, and qPCR analysis of DNA-damage and apoptosis-related genes were also performed.</p><p><strong>Results: </strong>Biodistribution and autoradiography confirmed that the ¹⁷⁷Lu- and ²²⁵Ac-labeled ligand effectively bound to pretargeted GPA33(+) xenografts when co-administered. High therapeutic indices were maintained across treatment groups, with autoradiography showing general overlap of co-injected probes. Combination therapy demonstrated comparable efficacy to monotherapies. At 150 d post-treatment, no treatment group had reached median survival; 5/9 mice receiving the cocktail (62.9 MBq ¹⁷⁷Lu + 18.5 kBq ²²⁵Ac) were alive, including two tumor-free. In comparison, 4/8 mice in the ¹⁷⁷Lu group and 8/10 in the ²²⁵Ac group survived, with 3 and 5 tumor-free animals, respectively. Combination therapy was well tolerated, showing no significant adverse effects on body weight or blood cell counts compared to healthy controls. Combined administration was safe up to 62.9 MBq ¹⁷⁷Lu + 37 kBq ²²⁵Ac, resulting in 10/10 histological cures.</p><p><strong>Conclusions: </strong>Our findings confirm the feasibility of a combined ¹⁷⁷Lu and ²²⁵Ac DOTA-PRIT in mice with established SW1222 xenografts, demonstrating tolerability and effectiveness comparable to monotherapy at equivalent average absorbed tumor doses.</p>","PeriodicalId":22932,"journal":{"name":"Theranostics","volume":"16 11","pages":"5898-5910"},"PeriodicalIF":13.3,"publicationDate":"2026-04-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13141694/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147842699","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":"Small molecules targeting the PD-1/PD-L1 axis for cancer immunotherapy.","authors":"Jia-Yi Yin, Hui-Min Liu, Shao-Long Li, Xin-Qian Ji, Jun-Jie Wang, Meng-Jie Fu, Cong-Jun Liu, Ning Wang, Guo-Liang Lu, Yan Li, Hong-Min Liu, Yi-Chao Zheng, Xing-Jie Dai, Ying Liu","doi":"10.7150/thno.130935","DOIUrl":"https://doi.org/10.7150/thno.130935","url":null,"abstract":"<p><p>PD-1/PD-L1 pathway, a key immune checkpoint, triggers T-cell exhaustion via binding and aiding tumor immune evasion. Although several anti-PD-1/PD-L1 monoclonal antibodies (mAbs) have been granted food and drug administration (FDA) approval, their high cost, poor oral bioavailability, and potential immunogenicity have led to a shift in research toward small molecules. This review summarizes the structure and function of PD-1/PD-L1 and, based on the PD-1/PD-L1 signaling process, focuses on three major classes of related compounds: small molecule inhibitors inducing PD-L1 dimerization or blocking PD-1/PD-L1 binding; PD-L1 degraders (e.g., Proteolysis-targeting chimeras (PROTACs) and Lysosome-targeting chimeras (LYTACs)) via the ubiquitin-proteasome or lysosomal pathway, overcoming membrane protein targeting; and dual-target inhibitors that enhance therapeutic efficacy by exerting synergistic effects. While small molecule drugs have advantages over monoclonal antibodies, including oral administration and reduced immunogenicity, they face drug resistance and toxicity challenges. This review aims to provide insights into the discovery of safe and effective antitumor immunotherapeutic agents.</p>","PeriodicalId":22932,"journal":{"name":"Theranostics","volume":"16 11","pages":"6051-6080"},"PeriodicalIF":13.3,"publicationDate":"2026-04-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13142127/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147843122","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":"Mechanistic role of APOE lipidation in Alzheimer's disease pathogenesis.","authors":"Dong Yan Zhang, Jian Wang, Nikolay V Dokholyan","doi":"10.7150/thno.131926","DOIUrl":"https://doi.org/10.7150/thno.131926","url":null,"abstract":"<p><p>The apolipoprotein E (APOE) <i>ε</i>4 allele is the primary genetic driver of late-onset Alzheimer's disease (AD), a complex neurodegenerative disorder characterized by the interplay of amyloid-β (Aβ) accumulation, tau pathology, neuroinflammation, and lipid metabolism dysfunction. Emerging evidence suggests that these pathological hallmarks are fundamentally linked to deficits in neuroplasticity and the continuous turnover of synapses. A growing body of evidence highlights APOE lipidation, a process by which APOE is loaded with lipids via cellular transporters such as ABCA1, as a key determinant of APOE function and toxicity. While lipidated APOE2 and APOE3 facilitate cholesterol transport and Aβ clearance, lipid-poor APOE4 is associated with impaired receptor-mediated clearance of Aβ, disrupted microglial function, increased neuroinflammation, and synaptic deficits. Furthermore, APOE lipidation status differentially influences tau pathology, potentially linking cholesterol dysregulation to tau hyperphosphorylation and aggregation. Here, we systematically examine the mechanistic role of APOE lipidation in AD pathogenesis, focusing on its effects on Aβ and tau pathology. We also discuss how dysregulation of APOE lipidation may serve as a central molecular mechanism connecting APOE4 to multiple pathological hallmarks of AD. This review examines how APOE lipidation is involved in amyloid-related and tau pathology in AD.</p>","PeriodicalId":22932,"journal":{"name":"Theranostics","volume":"16 11","pages":"5926-5950"},"PeriodicalIF":13.3,"publicationDate":"2026-04-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13142122/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147843162","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":"Edge-rich Cu-N₃ single atom nanozyme drives lipid switching to potentiate tumor catalytic therapy.","authors":"Xin Xing, Jiaji Yu, Yajie Zhang, Xue Chen, Liang Chen, Meng Du, Jie Ding, Zhiyi Chen, Li Li, Junjie Cheng","doi":"10.7150/thno.128026","DOIUrl":"https://doi.org/10.7150/thno.128026","url":null,"abstract":"<p><strong>Rationale: </strong>Tumor catalytic therapy represents a promising antitumor approach by inducing ferroptosis and overcoming apoptosis-related resistance mechanisms. Its efficacy is primarily dictated by the extent of membrane lipid peroxidation (LPO). However, tumor cells may evade ferroptosis through metabolic reprogramming that enriches monounsaturated fatty acids (MUFAs) in membrane lipids, thereby diminishing oxidative vulnerability. Hence, strategies that simultaneously enhance catalytic ROS production and reprogram lipid metabolism are required to address this challenge.</p><p><strong>Methods: </strong>To overcome this limitation, a novel Cu-N₃ single-atom nanozyme with edge enrichment (<i>ER</i>-Cu₁SAZyme) was developed, characterized by a hollow porous structure and catalytically active sites concentrated along the edges. This design optimizes atom utilization, increases local electronic density, and lowers the reaction energy barrier, thereby promoting potent intracellular reactive oxygen species (ROS) generation. To further sensitize tumors to ferroptosis, <i>ER</i>-Cu₁SAZyme was combined with sirolimus (Srl), an FDA-approved drug, to create the Srl/<i>ER</i>-Cu₁SAZyme nanomedicine for coordinated catalytic and metabolic regulation.</p><p><strong>Results: </strong>The Srl/<i>ER</i>-Cu₁SAZyme formulation simultaneously inhibits stearoyl-CoA desaturase 1 (SCD1)-mediated MUFA synthesis and upregulates ACSL4, thereby shifting the membrane lipid composition toward a ferroptosis-sensitive phenotype and enhancing nanozyme-induced LPO. This dual catalytic-metabolic strategy increases ferroptosis susceptibility while reducing metastatic potential linked to excessive membrane fluidity. In tumor-bearing mouse models, Srl/<i>ER</i>-Cu₁SAZyme treatment led to a 33-fold reduction in tumor volume compared to the untreated group, without observable systemic toxicity.</p><p><strong>Conclusions: </strong>These results highlight the effectiveness of integrating edge-enriched single-atom catalysis with lipid metabolic modulation to enhance ferroptosis-based tumor therapy. The Srl/<i>ER</i>-Cu₁SAZyme nanomedicine offers a safe and highly potent approach for dual catalytic-metabolic regulation in cancer treatment.</p>","PeriodicalId":22932,"journal":{"name":"Theranostics","volume":"16 11","pages":"6011-6031"},"PeriodicalIF":13.3,"publicationDate":"2026-04-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13142117/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147843210","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":"Unraveling the pleiotropic effects of CCR2-dependent signal transduction in fibrosis development.","authors":"Guozheng Sun, Jiaxing Wang, Jiayou Tang, Mingzhe Chen, Zhe Zhang, Huadong Zhao, Zhenxiao Jin, Xuezeng Xu, Yang Yang, Jincheng Liu","doi":"10.7150/thno.130426","DOIUrl":"https://doi.org/10.7150/thno.130426","url":null,"abstract":"<p><p>Fibrosis is a pathological process characterized by the abnormal deposition of connective tissue across multiple organ systems. Given the high prevalence of fibrotic diseases and the limited availability of clinical treatment options, it has emerged as a major challenge in contemporary medicine. Chronic inflammation is widely recognized as a common pathological basis of various fibrotic disorders. In fibrosis progression, CCR2 acts as a critical signaling hub, initiating cascade reactions and contributing to the formation of a complex regulatory network. Studies have demonstrated that in most organ fibrotic processes, CCR2 primarily exerts pro-fibrotic effect by recruiting inflammatory monocytes, activating fibroblasts, and promoting extracellular matrix deposition. However, the function of CCR2 is not unidimensional. It may also play a regulatory role in promoting fibrosis regression under specific tissue and pathological contexts. CCR2 signaling exhibits dual regulatory properties at different stages of liver fibrosis. CCR2 promotes injury in the early phase, while participating in fibrosis reversal by mediating macrophage transition toward a reparative phenotype and facilitating extracellular matrix degradation. This stage-dependent behavior suggests that inappropriate timing of intervention may disrupt repair process, and the functional redundancy of the chemokine system may trigger compensatory adaptations. Together, these factors constitute the core translational challenges facing CCR2-targeted therapeutic strategies. This article systematically reviews the complex regulatory network and pivotal role of CCR2 signaling in fibrosis progression, summarizes the latest advances in the diagnosis and treatment of clinically relevant fibrotic diseases associated with this pathway, analyzes the specific challenges in translating CCR2-targeted therapies into clinical practice, and outlines future research directions.</p>","PeriodicalId":22932,"journal":{"name":"Theranostics","volume":"16 11","pages":"5951-5991"},"PeriodicalIF":13.3,"publicationDate":"2026-04-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13142124/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147843143","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":"Biomaterials in pancreatic surgery: progress and challenges in preoperative, intraoperative and postoperative care.","authors":"Qiang Guo, Shuwen Xiao, Xing Huang, Shengzhong Hou, Binxu Qiu, Ning Xia, Kai Xiao, Zhenyu Duan, Bole Tian, Kui Luo","doi":"10.7150/thno.131228","DOIUrl":"https://doi.org/10.7150/thno.131228","url":null,"abstract":"<p><p>Pancreatic surgery is frequently associated with exceptionally high risks due to the intricate anatomical structure, and elevated enzymatic activity, which can lead to severe postoperative complications. With deep integration of material science and clinical medicine, biomaterials have been progressively applied in pancreatic surgery across the entire perioperative period, not only improved the sensitivity and specificity of diagnosis but also prevent postoperative complications and accelerated rehabilitation. Thus, this review systematically summarizes state-of-art development, efficacy, safety, challenges and perspective of biomaterials when they are applied in pancreatic surgery at preoperative, intraoperative and postoperative stages, which not only help clinicians choose materials-derived products for their surgical operations, but also provide insights for material scientists into developing advanced materials for pancreatic surgery.</p>","PeriodicalId":22932,"journal":{"name":"Theranostics","volume":"16 11","pages":"5856-5897"},"PeriodicalIF":13.3,"publicationDate":"2026-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13141714/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147843225","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":"Engineering Tfh-Specific Nanoadjuvant to Counteract Bile Acid-Induced Mitophagy and Vaccine Hyporesponsivenes.","authors":"Huimin Wu, Zhigang Zheng, Haifeng Chen, Jinchuan Liu, Xiandong Zeng, Xiaochun Huang, Xu Fang, Junlin Zhu, Yuanjia Tang, Jun Deng, Qiang Xia, Feng Xue","doi":"10.7150/thno.125668","DOIUrl":"https://doi.org/10.7150/thno.125668","url":null,"abstract":"<p><p>Bile acids were involved in vaccine response and modulating immune cells. Follicular helper T (Tfh) cells serve a critical immunoregulatory function in vaccine response. However, the precise role of bile acids in modulating Tfh cells and the underlying mechanisms remain unclear. Nano-adjuvant targeting and modulating Tfh cells may offer a promising strategy to improve vaccine response. In this study, we first discovered that 3-oxo-lithocholic acid (3-oxoLCA) impaired the differentiation and function of cultured Tfh vacells both in human and mice <i>in vitro</i>. <i>In vivo</i>, 3-oxoLCA gavage significantly reduced the proportion of Tfh cells in spleen and antibody responses in WT mice under NP-OVA immunization. Mechanistically, 3-oxoLCA promoted intracellular mitophagy of Tfh cells by RNA sequencing analysis and rescue experiment. Leveraging these insights, we engineered a mitophagy-inhibiting, Tfh cells-targeted nano-adjuvant (M-1@NP) decorated with anti-CXCR5 and anti-ICOS antibodies to precisely increased Tfh cells generation and function. This nanoplatform not only boosted cultured Tfh cells generation <i>in vitro</i> but also amplified germinal center (GC) responses and specific antibody production in immunized mice, with high targeting specificity and biocompatibility. In conclusion, 3-oxoLCA inhibited the differentiation and function of mouse and human Tfh cells by promoting intracellular mitophagy. Tfh cells-targeted nano-adjuvant effectively enhanced the ratio and functions of Tfh cells. M-1@NP represents a potentially valuable option for promoting vaccine response in clinical applications.</p>","PeriodicalId":22932,"journal":{"name":"Theranostics","volume":"16 10","pages":"5741-5758"},"PeriodicalIF":13.3,"publicationDate":"2026-03-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13081164/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147699834","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":"Human atrial extracellular vesicles suppress NLRP3 inflammasome activation and profibrotic signaling in a patient-specific iPSC model of postoperative atrial fibrillation.","authors":"Noreen Ahmed, Bin Ye, Wenbin Liang, Buu-Khanh Lam, Fraser Rubens, Saad Khan, David Courtman, Duncan John Stewart, Darryl Raymond Davis","doi":"10.7150/thno.127433","DOIUrl":"https://doi.org/10.7150/thno.127433","url":null,"abstract":"<p><strong>Background: </strong>Postoperative atrial fibrillation (AF) remains a common and morbid complication of cardiac surgery, driven by inflammation and fibrosis for which targeted therapies are limited. Conventional antiarrhythmic and anticoagulant strategies have little impact on its incidence or recurrence. We previously demonstrated that a single intracardiac injection of extracellular vesicles (EVs) derived from human heart explant-derived cells prevents postoperative AF in preclinical models. The present study aimed to elucidate the mechanisms underlying this protective effect in human cells.</p><p><strong>Methods: </strong>Induced pluripotent stem cells (iPSCs) were generated from circulating mononuclear cells obtained from cardiac surgery patients at high and low risk for postoperative AF, then differentiated into atrial fibroblasts. These cells were compared with primary human atrial fibroblasts isolated from surgical tissue. Clinical-grade cardiac EVs were manufactured from heart explant-derived cells and characterized for size, surface markers, and microRNA cargo. Both iPSC-derived and primary fibroblasts were exposed to inflammatory (IL-6, TGF-β1, lipopolysaccharide) and fibrotic stimuli, with or without EV treatment. Inflammasome activation and cytokine secretion were assessed by transcript and protein analyses.</p><p><strong>Results: </strong>iPSC-derived and primary atrial fibroblasts exhibited comparable antigenic and functional profiles and efficiently internalized cardiac EVs. EV treatment markedly suppressed activation of the NLRP3 inflammasome following lipopolysaccharide and nigericin stimulation, resulting in reduced secretion of Caspase-1, IL-1β, and IL-18 and corresponding transcript downregulation. EVs also attenuated IL-6 and TGF-β1 induced fibroblast proliferation, confirming their anti-inflammatory and antifibrotic effects across cell sources and patient risk groups.</p><p><strong>Conclusions: </strong>This study establishes a patient-specific human cellular model of cardiac fibrosis, a key determinant of postoperative AF, and identifies heart-derived EVs as potent suppressors of inflammasome activation and profibrotic signaling. These findings provide mechanistic insight into the anti-inflammatory and antifibrotic actions of cardiac EVs and support their further development as a cell-free biologic for the prevention of postoperative AF.</p>","PeriodicalId":22932,"journal":{"name":"Theranostics","volume":"16 11","pages":"5804-5815"},"PeriodicalIF":13.3,"publicationDate":"2026-03-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13141743/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147843180","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":"Discovery of a novel Nrf2 activator that modulates mitochondrial function in neurons by regulating DHRS3-Nrf2 interaction after ischemic stroke.","authors":"Xiaohui Sun, Zhaofeng Liu, Huanhuan An, Hengwei Xu, Fangxia Zou, Jing Lu, Xiaofan Zhang, Xinyu Han, Ziwei Song, Yanli Sun, Wenyan Wang, Hongbo Wang, Jianzhao Zhang, Yunjie Wang, Jingwei Tian","doi":"10.7150/thno.128602","DOIUrl":"https://doi.org/10.7150/thno.128602","url":null,"abstract":"<p><p><b><i>Rationale:</i></b> Given the crucial role of the Nrf2 pathway in cellular adaptability to stress, targeting small-molecule activation of Nrf2 represents a promising therapeutic strategy for acute ischemic stroke (AIS). However, the clinical translation of existing Nrf2 activators is hindered by adverse effects, such as liver damage, and none are currently approved for AIS. Therefore, we aimed to develop a novel Nrf2 activator that specifically activates neuronal Nrf2 while mitigating adverse effects, with the goal of providing a lead compound for AIS. <b><i>Methods:</i></b> We validated the anti-AIS effects and mitochondrial protective functions of the novel Nrf2 activator Cpd.51 through multiple <i>in vivo</i> and <i>in vitro</i> experiments. Mechanistic studies involving surface plasmon resonance, cellular thermal shift assay, co-immunoprecipitation, chromatin immunoprecipitation, GST pull-down, and RNA sequencing were used to determine how Cpd.51 activates Nrf2. A comparative toxicological evaluation was conducted to demonstrate its superior safety profile over parent compound (Omaveloxolone). <b><i>Results:</i></b> Cpd.51 exhibited favorable blood-brain barrier permeability, improved safety profile, enhanced mitochondrial function protection and significant neuroprotective effect through the specific activation of neuronal Nrf2. Mechanistically, Cpd.51 interacted with Cys151 and Gly148 in the BTB domain of Keap1, inhibiting Nrf2 degradation, consequently suppressing the transcription of its downstream target DHRS3, a member of the short-chain dehydrogenase/reductase family. Furthermore, Cpd.51 exerted additional Nrf2-activating activity by disrupting protein-protein interactions between Nrf2 and DHRS3. <b><i>Conclusions:</i></b> Our work identified Cpd.51 as a novel and safe Nrf2 activator and unveils a unique feedback mechanism involving Nrf2-DHRS3 interaction, providing a new therapeutic avenue for AIS.</p>","PeriodicalId":22932,"journal":{"name":"Theranostics","volume":"16 10","pages":"5713-5740"},"PeriodicalIF":13.3,"publicationDate":"2026-03-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13081163/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147699822","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":"Sensitization strategy for sonodynamic therapy.","authors":"Sinong Li, Ziyi Yang, Ying Zhang, Genyuan Zhang, Zoujuan Cai, Yihan Xie, Zhiqun Bai, Jin Sun, Hongzan Sun, Zhiguang Chen, Liang Sang","doi":"10.7150/thno.130498","DOIUrl":"https://doi.org/10.7150/thno.130498","url":null,"abstract":"<p><p>Sonodynamic therapy (SDT), a tumor treatment modality characterized by deep tissue penetration and high spatiotemporal precision, faces multiple challenges in clinical translation, including suboptimal sonosensitizer efficiency, suppression by the tumor microenvironment (TME), and insufficient induction of antitumor immune responses. This paper systematically reviews the multifaceted sensitization strategies of SDT, breaking away from traditional single-optimization approaches to establish a comprehensive synergistic enhancement framework spanning the entire chain involving \"material design-microenvironment regulation-immune remodeling-synergistic therapy.\" In sonosensitizer engineering, current research emphasizes advanced design strategies-including defect engineering, heterostructure construction, and piezoelectric materials-to markedly enhance reactive oxygen species (ROS) generation through band structure modulation and mechano-electro-chemical coupling effects. To overcome the TME-associated constraints, a series of innovative strategies such as hypoxia alleviation, antioxidant depletion, metabolic reprogramming and bacteria-mediated targeted delivery have been developed to mitigate ROS scavenging and improve tumor selectivity. Furthermore, this review summarizes how SDT is integrated with multiple synergistic modalities such as chemodynamic therapy, phototherapy, immunotherapy, and ferroptosis/cuproptosis induction and systematically elucidates the underlying mechanisms and therapeutic potential of these combinations in triggering immunogenic cell death, reversing tumor immunosuppression, and ultimately enabling diagnostic-therapeutic integration. Despite persistent challenges in nanodelivery, controllable ROS generation, and clinical standardization, this review highlights that the development of multimodal, responsive, and biohybrid platforms is driving SDT toward a new paradigm of precise and intelligent cancer treatment. Collectively, these findings provide a systematic strategic blueprint with translational potential for treating deep-seated and drug-resistant solid tumors.</p>","PeriodicalId":22932,"journal":{"name":"Theranostics","volume":"16 10","pages":"5685-5712"},"PeriodicalIF":13.3,"publicationDate":"2026-03-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13081186/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147699413","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}