{"title":"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","doi":"10.7150/thno.106811","DOIUrl":"10.7150/thno.106811","url":null,"abstract":"<p><p><b>Background:</b> 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). <b>Methods:</b> C-dots were combined with Cu<sub>5.4</sub>O USNPs to synthesize a cost-effective nanozyme, Cu<sub>5.4</sub>O@CNDs, which mimics the activity of cascade enzymes. The <i>in vitro</i> evaluation demonstrated the ROS scavenging and anti-inflammatory capacity of Cu<sub>5.4</sub>O@CNDs. The therapeutic potential of Cu<sub>5.4</sub>O@CNDs was evaluated <i>in vivo</i> using mouse models of hepatic ischemia/reperfusion injury and LPS/D-GalN induced hepatitis, with transcriptome analysis conducted to clarify the mechanism underlying hepatoprotection. <b>Results:</b> The Cu<sub>5.4</sub>O@CNDs demonstrated superoxide dismutase (SOD) and catalase (CAT) enzyme activities, as well as hydroxyl radical (·OH) scavenging capabilities, effectively mitigating ROS <i>in vitro</i>. Furthermore, the Cu<sub>5.4</sub>O@CNDs exhibited remarkable targeting efficacy towards inflammation cells induced by H<sub>2</sub>O<sub>2</sub> and hepatic tissues in murine models of hepatitis, alongside exhibiting favorable biocompatibility in both <i>in vitro</i> and <i>in vivo</i> settings. Moreover, it has been demonstrated that Cu<sub>5.4</sub>O@CNDs effectively scavenged ROS, thereby enhancing cell survival <i>in vitro</i>. Additionally, Cu<sub>5.4</sub>O@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. <b>Conclusions:</b> In summary, this study demonstrates that Cu<sub>5.4</sub>O@CNDs exhibit significant potential for the treatment of various acute liver injury conditions, suggesting their promise as an intervention strategy for clinical application.</p>","PeriodicalId":22932,"journal":{"name":"Theranostics","volume":"15 12","pages":"5592-5615"},"PeriodicalIF":12.4,"publicationDate":"2025-04-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12068305/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144052522","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}
TheranosticsPub Date : 2025-04-21eCollection Date: 2025-01-01DOI: 10.7150/thno.109994
Chaofan Liu, Xi Wang, Qinyu Li, Xintao Gao, Kai Zeng, Beining Li, Jianping Miao, Bolong Zheng, Jihong Liu, Zhihua Wang, Xianglin Yuan, Bo Liu
{"title":"Apolipoprotein E promotes primary resistance to AR-targeted therapy via inducing TRIM25-mediated AR ubiquitination and sensitizes immunotherapy in prostate cancer.","authors":"Chaofan Liu, Xi Wang, Qinyu Li, Xintao Gao, Kai Zeng, Beining Li, Jianping Miao, Bolong Zheng, Jihong Liu, Zhihua Wang, Xianglin Yuan, Bo Liu","doi":"10.7150/thno.109994","DOIUrl":"10.7150/thno.109994","url":null,"abstract":"<p><p><b>Rationale:</b> Prostate cancer (PCa) growth is facilitated by the androgen receptor (AR) and its downstream signaling pathways, making AR-targeted therapy crucial for treating advanced stages. Despite this, the response to AR-targeted therapies is inconsistent, with a significant proportion of patients even exhibiting unresponsiveness to therapy from the outset, known as primary resistance. Therefore, a refined categorization framework is imperative for the timely detection of resistant phenotypes and the exploration of novel therapeutic avenues. <b>Methods:</b> Tissue microarrays and clinical cohorts were employed to delineate the impact of APOE on the prognostic outcomes and therapeutic resistance in PCa patients. Employing flow cytometry, immunoprecipitation, and mass spectrometry, we dissected the molecular underpinnings of APOE's role in conferring resistance to AR-targeted interventions. Single-cell RNA sequencing elucidated the intricate transcriptomic profiles of PCa with elevated APOE expression. Additionally, the therapeutic potential of anti-PD-L1 agents in treating PCa with APOE induction was rigorously assessed. <b>Results:</b> In this study, we elucidated the pivotal role of APOE in mediating primary resistance to AR-targeted therapy in PCa through the suppression of AR signaling pathways. Mechanistically, APOE was found to enhance the ubiquitination and subsequent degradation of AR by mediating the interaction between the E3-ligase TRIM25 and AR, concurrently dampening the transcriptional activity of AR. Additionally, elevated APOE expression was correlated with an augmented response to anti-PD-L1 treatment, hinting at the therapeutic advantage of immunotherapy in APOE-high PCa contexts. <b>Conclusions:</b> APOE expression could serve as a prognostic biomarker, pivotal for forecasting responses to both AR-targeted therapy and immunotherapy, thereby offering an innovative strategy for the personalized selection of treatment modalities in PCa.</p>","PeriodicalId":22932,"journal":{"name":"Theranostics","volume":"15 12","pages":"5572-5591"},"PeriodicalIF":12.4,"publicationDate":"2025-04-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12068304/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144043442","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}
TheranosticsPub Date : 2025-04-21eCollection Date: 2025-01-01DOI: 10.7150/thno.106913
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
{"title":"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","doi":"10.7150/thno.106913","DOIUrl":"10.7150/thno.106913","url":null,"abstract":"<p><p><b>Rationale:</b> 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. <b>Methods:</b> A tannic acid-crosslinked gelatin-based hydrogel scaffold with the addition of Mn<sup>2+</sup> 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. <b>Results:</b> 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. <b>Conclusion:</b> The findings demonstrate the potential of a multifunctional, high-strength supramolecular hydrogel loaded with dual drugs for the functional regeneration of AF tissue.</p>","PeriodicalId":22932,"journal":{"name":"Theranostics","volume":"15 12","pages":"5756-5771"},"PeriodicalIF":12.4,"publicationDate":"2025-04-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12068310/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144050166","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}
TheranosticsPub Date : 2025-04-21eCollection Date: 2025-01-01DOI: 10.7150/thno.108654
Mingjuan Lei, Yiu To Yeung, Wenna Nie, Ran Yang, Jian Li, Hanyong Chen, Ran Zhao, Kangdong Liu, Zigang Dong
{"title":"AHCYL1 mediates the tumor-promoting effect of PREX2 in non-small cell lung carcinoma.","authors":"Mingjuan Lei, Yiu To Yeung, Wenna Nie, Ran Yang, Jian Li, Hanyong Chen, Ran Zhao, Kangdong Liu, Zigang Dong","doi":"10.7150/thno.108654","DOIUrl":"10.7150/thno.108654","url":null,"abstract":"<p><p><b>Rationale:</b> As the most common form of lung cancer, non-small cell lung cancer (NSCLC) is still a challenging disease. Even though molecular-targeted drugs have greatly benefited NSCLC patients, the limited number of effective targets and the emergence of drug resistance necessitate further research to identify new candidates and improve clinical outcomes. Phosphatidylinositol-3,4,5-triphosphate-dependent RAC exchange factor-2 (PREX2) is highly expressed in multiple cancer types and poses high mutation frequency in lung cancer. However, the study of PREX2 in lung cancer, especially NSCLC, is few and unclear, thus, the role of PREX2 and the regulatory mechanism of PREX2 in NSCLC is worthy of further investigation. <b>Methods:</b> To determine the tumor-promoting effects of PREX2 in NSCLC, we established PREX2 knockdown NSCLC cells, then assessed cell growth in <i>vitro</i> and in cell-derived xenograft (CDX) mouse model. Furtherly, we used the urethane-induced lung carcinogenesis mouse model to confirm the significance of PREX2 <i>in vivo</i>. Additionally, we identified AHCYL1 as a novel PREX2-interacting protein through pull-down assay and liquid chromatography with tandem mass spectrometry (LC-MS/MS) and investigated the mechanisms of PREX2 GEF activity regulated by AHCYL1 using various molecular biology assays, including western blotting, <i>in vitro</i> GEF assay and active RAC1 pull-down assay. <b>Results:</b> Our study suggests that PREX2 and AHCYL1 both promote NSCLC cell growth and proves that AHCYL1 enhances the GEF activity of PREX2 by alleviating the mutual inhibition between PREX2 and PTEN. Consequently, AHCYL1 intensifies the tumor-promoting effects of PREX2 in NSCLC. <b>Conclusion:</b> Overall, our results indicate that PREX2 and AHCYL1 promote lung cancer development and reveal a novel regulatory mechanism of PREX2 GEF activity by AHCYL1, which will contribute to the understanding of NSCLC pathogenesis and offer new targets and strategies for the diagnosis and treatment of NSCLC.</p>","PeriodicalId":22932,"journal":{"name":"Theranostics","volume":"15 12","pages":"5772-5789"},"PeriodicalIF":12.4,"publicationDate":"2025-04-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12068309/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144052519","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":"Spatially segregated APOE<sup>+</sup> macrophages restrict immunotherapy efficacy in clear cell renal cell carcinoma.","authors":"Qintao Ge, Jialin Meng, Zhongyuan Wang, Aihetaimujiang Anwaier, Jiahe Lu, Xi Tian, Yue Wang, Jianfeng Yang, Hailiang Zhang, Dingwei Ye, Wenhao Xu","doi":"10.7150/thno.109097","DOIUrl":"https://doi.org/10.7150/thno.109097","url":null,"abstract":"<p><p><b>Background:</b> Immunotherapy has revolutionized cancer treatment and holds great potential for them, including metastatic clear cell renal cell carcinoma (ccRCC). However, immune resistance remains a major obstacle, limiting its efficacy and durability. Understanding the mechanisms of immune tolerance in the tumor microenvironment (TME) is pivotal for overcoming these challenges and enhancing therapeutic outcomes. <b>Methods:</b> Over 2000 samples, including a real-world cohort of 230 advanced ccRCC patients treated with immune checkpoint blockade (ICB) were analyzed. Single-cell RNA sequencing data from 13 tumor regions were categorized into ICB-exposed, ICB-resistant, and ICB-responsive groups. Multiple robust algorithms and multiplex immunofluorescence were used to explore TME composition and macrophage heterogeneity. Spatial communication dynamics were further investigated. <i>In vitro</i> experiments were performed to evaluate the impact of SPP1 on 786-O and 769-P cells. Co-culture experiments with THP-1-derived macrophages, followed by Western blot, flow cytometry, and functional assays, were performed to investigate SPP1-mediated macrophage polarization and its impact on tumor progression. <b>Results:</b> The results revealed an elevated presence of Apolipoprotein E (APOE)<sup>+</sup> macrophages in ICB-resistant ccRCC. Notably, higher APOE<sup>+</sup> macrophage proportion indicated shorter prognosis and worse response to ICB (<i>P</i> < 0.001). Elevated expression of CCAAT Enhancer Binding Protein Delta (CEBPD) was markedly linked to several immunosuppressive pathways, hindering T cell recruitment, promoting exhaustion, ultimately diminishing poorer prognosis and worse ICB efficacy. Meanwhile, upregulated Secreted Phosphoprotein 1 (SPP1) significantly enhances the proliferation, clonal formation, and migration of ccRCC cells. Tumor-derived SPP1. Additionally, SPP1 signaling from malignant cells appeared to recruit APOE<sup>+</sup> macrophages to tumor margins, and promotes macrophage polarization into APOE<sup>+</sup> M2-like macrophages. In the vicinity of the tumor, these APOE<sup>+</sup> macrophages shape immunosuppressive TME by releasing abundant TGF-β signals, limiting anti-tumor effector T cells activity in ICB-resistant tumors, and contributing to tumor progression. <b>Conclusion:</b> This study reveals the critical role of APOE<sup>+</sup> macrophages in promoting immune suppression and resistance to ICB therapy in ccRCC. By promoting T cell exhaustion and immunosuppressive signaling, particularly via localized TGF-β, these spatially segregated macrophages undermine treatment efficacy. Targeting APOE<sup>+</sup> macrophages, especially in conjunction with ICB, presents a promising strategy to overcome immune resistance and enhance outcomes for ccRCC patients.</p>","PeriodicalId":22932,"journal":{"name":"Theranostics","volume":"15 11","pages":"5312-5336"},"PeriodicalIF":12.4,"publicationDate":"2025-04-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12036886/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144016107","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}
TheranosticsPub Date : 2025-04-13eCollection Date: 2025-01-01DOI: 10.7150/thno.111923
Shangyao Qin, Xiao Huang, Yimin Yuan, Hong Liu, Jiali Li, Ziwei Dai, Zhida Lan, Yingyan Pu, Cheng He, Zhida Su
{"title":"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","doi":"10.7150/thno.111923","DOIUrl":"https://doi.org/10.7150/thno.111923","url":null,"abstract":"<p><p><b>Rationale:</b> 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. <b>Methods:</b> 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). <b>Results:</b> Both <i>in vitro</i> and <i>in vivo</i> 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. <b>Conclusions:</b> 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.</p>","PeriodicalId":22932,"journal":{"name":"Theranostics","volume":"15 11","pages":"5402-5419"},"PeriodicalIF":12.4,"publicationDate":"2025-04-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12036888/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143998841","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}
TheranosticsPub Date : 2025-04-13eCollection Date: 2025-01-01DOI: 10.7150/thno.107162
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
{"title":"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","doi":"10.7150/thno.107162","DOIUrl":"https://doi.org/10.7150/thno.107162","url":null,"abstract":"<p><p><b>Rationale:</b> 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. <b>Methods:</b> We created \"Magnetic Sculpture-like (MASK) Cells\" by treating tumor cells with high-concentration FeCl<sub>3</sub>, inducing rapid morphological fixation without traditional chemical crosslinking. MASK cells were characterized for proliferative capacity, biomolecule retention, and magnetic properties. Vaccine efficacy was tested <i>in vitro</i>, in melanoma-bearing mouse models, and through spatial transcriptomic profiling of tumor microenvironments. Combination therapy with anti-PD-1 was further evaluated. <b>Results:</b> 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, FeCl<sub>3</sub> sculpting imparts magnetism to cells, enabling directional navigation to tumors using magnetic fields and enhanced <i>in situ</i> 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. <b>Conclusion:</b> MASK cells represent a promising new approach for targeted, patient-specific anti-tumor therapeutics.</p>","PeriodicalId":22932,"journal":{"name":"Theranostics","volume":"15 11","pages":"5358-5380"},"PeriodicalIF":12.4,"publicationDate":"2025-04-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12036876/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144038469","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}