Theranostics最新文献

{"title":"MRI guided copper deprivator activated immune responses and suppressed angiogenesis for enhanced antitumor immunotherapy.","authors":"Yinfeng Wang, Peng Wang, Huimin Li, Miao Yan, Feixue Ni, Li Zhang, Zhen Zhao, Wenjuan Gao, Guilong Zhang","doi":"10.7150/thno.102556","DOIUrl":"10.7150/thno.102556","url":null,"abstract":"<p><p><b>Background:</b> Copper plays an important role in the regulation of PD-L1, suggesting that reducing copper levels within tumors may enhance anti-cancer immunotherapy. <b>Methods:</b> Tumor microenvironment responsive copper nanodeprivator (TMECN) was developed for enhancing immunotherapy of tumor via the cross-link of mercaptopolyglycol bipyridine and dimercaptosuccinic acid modifying FePt nanoalloy using the disulfide bond. <b>Results:</b> Upon entering tumor cells, the disulfide bond in TMECN is cleaved by the overexpressed glutathione, exposing abundance of sulfhydryl groups. Next, TMECN actively captured copper ions in the cancer cells, which triggered the self-assembly of TMECN. The reduced copper not only inhibited tumor neovascularization and PD-L1 transcription but also promoted the ubiquitination and degradation of PD-L1, blocking tumor immune escape. In addition, TMECN catalyzed Fenton reaction and produced reactive oxygen species (ROS) in cancer cells, inducing immunogenic cell death (ICD) of tumor. The inhibition of PD-L1 and the activation of ICD synergistically promoted cytotoxic T lymphocyte infiltration for tumor, evoked robust antitumor immune responses. In addition, the self-assembly of TMECN in tumor induced T₁ to T₂ switchable contrast imaging, which significantly improved accurate diagnosis of tumor. <b>Conclusion:</b> TMECN could effectively inhibit tumor growth and metastases, meanwhile improve MRI contrast enhancement of tumor. The project will offer a simple strategy for enhancing MRI-guided antitumor immunotherapy.</p>","PeriodicalId":22932,"journal":{"name":"Theranostics","volume":"15 2","pages":"546-559"},"PeriodicalIF":12.4,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11671392/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142915534","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":"tRNA-derived small RNAs in disease immunity.","authors":"Hongyuan Jia, Linling Zhang","doi":"10.7150/thno.102650","DOIUrl":"10.7150/thno.102650","url":null,"abstract":"<p><p>Recently, members of a unique species of non-coding RNA, known as transfer RNA-derived small RNAs (tsRNAs) have been reported to serve multiple molecular functions, including in cells that mediate immunity. Because of their low molecular weights, tsRNAs were previously difficult to detect and were thus overlooked, until now. In this review, we delve into the biogenesis of tsRNAs and their diverse biological functions, ranging from transcriptional regulation to modulation of mRNA translation. We highlight the current evidence demonstrating their involvement in the immune response, as well as how tsRNAs modulate immunity to influence tumor growth and spread, autoimmune disease pathology and infection by pathogens. We surmise that tsRNAs are likely informative as diagnostic markers of cellular homeostasis and disease, and that therapeutic targeting of tsRNAs could be beneficial for a range of human diseases. Improved knowledge on the functions for tsRNAs in the mammalian immune system will enable us to leverage tsRNAs for their effective clinical use as treatments for human health challenges.</p>","PeriodicalId":22932,"journal":{"name":"Theranostics","volume":"15 1","pages":"245-257"},"PeriodicalIF":12.4,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11667222/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142915549","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 indole analogue Tc3 as a potent pyroptosis inducer and identification of its combination strategy against hepatic carcinoma.","authors":"Xiao Hu, Xiaomei Tang, Xiaoman Tian, Xing Lv, Yuanyuan Zhang, Yingyue Pang, Weilong Deng, Yali Wang, Changliang Shan, Luqing Shang","doi":"10.7150/thno.102228","DOIUrl":"10.7150/thno.102228","url":null,"abstract":"<p><p><b>Rationale:</b> Hepatic carcinoma, one of the most malignant cancers in the world, has limited success with immunotherapy and a poor prognosis in patients. While pyroptosis is considered as a promising immunotherapy strategy for tumors, it still suffers from a lack of effective inducers. <b>Methods:</b> We designed, synthesized and screened an indole analogue, <b>Tc3</b>, featuring a 2, 4-thiazolidinedione substituted indole scaffold. Western blotting, qPCR and immunofluorescence were employed to detect the levels of pyroptosis pathway induced by <b>Tc3</b>. RNA sequencing was used to identify the mechanisms of <b>Tc3</b> in hepatic carcinoma. To validate anti-tumor effect of <b>Tc3</b>, we used CDXs and PDXs mouse models <i>in vivo</i>. Then, the syngeneic effects of <b>Tc3</b> with cisplatin and anti-PD-1 antibody were verified via western blotting, immunofluorescence, flow cytometry and ELISA. <b>Results:</b> Treatment with <b>Tc3</b> notably inhibited the growth of hepatic carcinoma both <i>in vitro</i> and <i>in vivo</i>. Mechanistically, <b>Tc3</b> inhibited the function of PRDX1 and up-regulated excessive ROS. Then, <b>Tc3</b> induced gasderminE-mediated pyroptosis by activating the endoplasmic reticulum stress. Tumor cells with high expression of GSDME achieved better responses to <b>Tc3</b>-therapy. <b>Tc3</b> also improved the efficacy of cisplatin against hepatic carcinoma. Additionally, superior synergistic treatment was observed when <b>Tc3</b> was combined with anti-PD-1 antibody. Notably, <b>Tc3</b> activated the tumor immune microenvironment (TIME) and enhanced CD8⁺ T cell infiltration in hepatic carcinoma. <b>Conclusions:</b> Collectively, we identified <b>Tc3</b> as a promising and effective compound for treating hepatic carcinoma and established its synergistic therapeutic strategy as a pyroptosis inducer.</p>","PeriodicalId":22932,"journal":{"name":"Theranostics","volume":"15 4","pages":"1285-1303"},"PeriodicalIF":12.4,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11729550/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143012094","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":"Unveiling urinary extracellular vesicle mRNA signature for early diagnosis and prognosis of bladder cancer.","authors":"Ning Sun, Zhaowei Zhang, Xiaoqing Yang, Jingqi Li, Qiang Li, Jingjing Kang, Yongchun Wei, Xiaoxuan Yu, Rui Du, Xiaoqin Hong, Guangming Liu, Hongmei Gao, Dingbin Liu","doi":"10.7150/thno.107213","DOIUrl":"10.7150/thno.107213","url":null,"abstract":"<p><p><b>Background:</b> Bladder cancer (BC) ranks as one of the most prevalent cancers. Its early diagnosis is clinically essential but remains challenging due to the lack of reliable biomarkers. Extracellular vesicles (EVs) carry abundant biological cargoes from parental cells, rendering them as promising cancer biomarkers. Herein, we revealed that urinary EVs (uEVs) mRNA signature could serve as non-invasive biomarker for the early diagnosis and prognostic assessment for BC. <b>Methods:</b> Transcriptomic sequencing was conducted to reveal the mRNA signature of EVs collected from normal cell line and different grades of BC cell lines. Candidate EV-mRNA biomarkers were further profiled using clinical urine samples (<i>n</i> = 97, including healthy controls, BC patients and post-surgery BC patients) by RT-qPCR. <b>Results:</b> Three mRNAs (SRGN, FLI1, and MACROH2A2) within uEV were identified as potential biomarkers for BC, providing an area under the receiver operating characteristic curve (AUC) of 0.973 for BC diagnosis. Moreover, the uEV-mRNA panel could discriminate early-stage BC patients from healthy controls with an AUC of 0.969. Finally, we found that the uEV-mRNAs were significantly down-regulated in the post-surgery urine samples of BC patients. <b>Conclusions:</b> Given the facile and non-intrusive nature of urine collection, the identified uEV-mRNAs could serve as potential liquid-biopsy biomarkers for the early diagnosis and prognosis of BC.</p>","PeriodicalId":22932,"journal":{"name":"Theranostics","volume":"15 4","pages":"1272-1284"},"PeriodicalIF":12.4,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11729556/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143012152","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":"Revolutionizing drug delivery: low-intensity pulsed ultrasound (LIPUS)-driven deep penetration into hypoxic tumor microenvironments of cholangiocarcinoma.","authors":"Sera Hong, Jaihwan Kim, Gujin Chung, Donghyuk Lee, Joon Myong Song","doi":"10.7150/thno.99981","DOIUrl":"10.7150/thno.99981","url":null,"abstract":"<p><p><b>Background:</b> Hypoxia is a major obstacle in the treatment of solid tumors because it causes immune escape and therapeutic resistance. Drug penetration into the hypoxic regions of tumor microenvironment (TME) is extremely limited. This study proposes using the unidirectional fluid flow property of low-intensity pulsed ultrasound (LIPUS) to overcome drug penetration limitations in the TME. LIPUS is gaining attention as a therapeutic modality for cancer owing to its safety and efficacy. <b>Methods:</b> LIPUS parameters, such as the intensity, duty cycle (DC), and duration, were optimized to enhance drug delivery into the hypoxic regions of the TME in cholangiocarcinoma (CCA). Transparent tumor imaging using the tissue optical clearing method (CLARITY) enabled 3D visualization and quantitative assessment of drug delivery and therapeutic efficacy in relation to blood vessels in an intact tumor at the micrometer level. The antitumor efficacy of LIPUS-assisted chemotherapy was evaluated in a CCA xenograft mouse model. <b>Results:</b> LIPUS significantly enhanced drug delivery efficacy into the hypoxic region of the TME in CCA. Under optimal conditions, i.e., a DC of 45% and a spatial-peak temporal-average intensity (Ispta) of 0.5 W/cm², drug penetration, including liposomal nanoparticles and chemotherapeutic agents gemcitabine and cisplatin, was improved by approximately 1.8-fold, resulting in a fivefold increase in apoptotic cancer cell death and a significant reduction in CCA growth. Notably, drug penetration and efficacy were more significantly affected by DC compared to the spatial-peak pulse-average intensity (Isppa). The efficacy saturated at Ispta values above 0.5 W/cm² under a 45% DC. Furthermore, we confirm that LIPUS induces non-thermal effects without causing cell damage, ensuring biosafety. These findings highlight the potential of LIPUS as a non-invasive strategy for treating hypoxic tumors. <b>Conclusion:</b> LIPUS adjuvant therapy promises improved cancer treatment outcomes and offers a safe and innovative therapeutic strategy for CCA and other hypoxic tumors.</p>","PeriodicalId":22932,"journal":{"name":"Theranostics","volume":"15 1","pages":"30-51"},"PeriodicalIF":12.4,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11667228/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142915546","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":"A molecularly distinct cell type in the midbrain regulates intermale aggression behaviors in mice.","authors":"Chunyang Li, Cheng Miao, Yao Ge, Jiaxing Wu, Panpan Gao, Songlin Yin, Pei Zhang, Hongbin Yang, Bo Tian, Wenqiang Chen, Xiao Qian Chen","doi":"10.7150/thno.101658","DOIUrl":"10.7150/thno.101658","url":null,"abstract":"<p><p><b>Rationale</b>: The periaqueductal gray (PAG) is a central hub for the regulation of aggression, whereas the circuitry and molecular mechanisms underlying this regulation remain uncharacterized. In this study, we investigate the role of a distinct cell type, <i>Tachykinin 2</i>-expressing (Tac2⁺) neurons, located in the dorsomedial PAG (dmPAG) and their modulation of aggressive behavior in mice. <b>Methods</b>: We combined activity mapping, <i>in vivo</i> Ca²⁺ recording, chemogenetic and pharmacological manipulation, and a viral-based translating ribosome affinity purification (TRAP) profiling using a mouse resident-intruder model. <b>Results</b>: We revealed that dmPAG^Tac2 neurons are selectively activated by fighting behaviors. Chemogenetic activation of these neurons evoked fighting behaviors, while inhibition or genetic ablation of dmPAG^Tac2 neurons attenuated fighting behaviors. TRAP profiling of dmPAG^Tac2 neurons revealed an enrichment of serotonin-associated transcripts in response to fighting behaviors. Finally, we validated these effects by selectively administering pharmacological agents to the dmPAG, reversing the behavioral outcomes induced by chemogenetic manipulation. <b>Conclusions</b>: We identify dmPAG^Tac2 neurons as critical modulators of aggressive behavior in mouse and thus suggest a distinct molecular target for the treatment of exacerbated aggressive behaviors in populations that exhibit high-level of violence.</p>","PeriodicalId":22932,"journal":{"name":"Theranostics","volume":"15 2","pages":"707-725"},"PeriodicalIF":12.4,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11671387/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142915552","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":"RNA nanotherapeutics for hepatocellular carcinoma treatment.","authors":"Yihang Yuan, Weijie Sun, Jiaqi Xie, Ziheng Zhang, Jing Luo, Xiangfei Han, Yongfu Xiong, Yang Yang, Yang Zhang","doi":"10.7150/thno.102964","DOIUrl":"10.7150/thno.102964","url":null,"abstract":"<p><p>Hepatocellular carcinoma (HCC) remains a leading cause of cancer-related mortality worldwide, particularly due to the limited effectiveness of current therapeutic options for advanced-stage disease. The efficacy of traditional treatments is often compromised by the intricate liver microenvironment and the inherent heterogeneity. RNA-based therapeutics offer a promising alternative, utilizing the innovative approach of targeting aberrant molecular pathways and modulating the tumor microenvironment. The integration of nanotechnology in this field, through the development of advanced nanocarrier delivery systems, especially lipid nanoparticles (LNPs), polymer nanoparticles (PNPs), and bioinspired vectors, enhances the precision and efficacy of RNA therapies. This review highlights the significant progress in RNA nanotherapeutics for HCC treatment, covering micro RNA (miRNA), small interfering RNA (siRNA), message RNA (mRNA), and small activating RNA (saRNA) mediated gene silencing, therapeutic protein restoration, gene activation, cancer vaccines, and concurrent therapy. It further comprehensively discusses the prevailing challenges within this therapeutic landscape and provides a forward-looking perspective on the potential of RNA nanotherapeutics to transform HCC treatment.</p>","PeriodicalId":22932,"journal":{"name":"Theranostics","volume":"15 3","pages":"965-992"},"PeriodicalIF":12.4,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11700867/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142955413","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":"Acylglycerol kinase inhibits macrophage anti-tumor activity via limiting mtDNA release and cGAS-STING-type I IFN response.","authors":"Qiuyang Du, Na Ning, Xiujuan Zhao, Feifan Liu, Si Zhang, Yuting Xia, Fei Li, Shijie Yuan, Xiaorong Xie, Mengdi Zhu, Zehan Huang, Zhaohui Tang, Jing Wang, Ran He, Xiang-Ping Yang","doi":"10.7150/thno.101298","DOIUrl":"https://doi.org/10.7150/thno.101298","url":null,"abstract":"<p><p><b>Background</b>: Tumor associated macrophages (TAMs) are critical components in regulating the immune statuses of the tumor microenvironments. Although TAM has been intensively studied, it is unclear how mitochondrial proteins such as AGK regulate the TAMs' function. <b>Methods</b>: We investigated the AGK function in TAMs using macrophage-specific <i>Agk</i> deficient mice with B16 and LLC syngeneic tumor models. Flow cytometry was used to evaluate the stemness and activation of CD8⁺ T cells. The enhanced release of mtDNA into the cytosol in the <i>Agk</i>-deficient BMDMs was measured by RT-PCR and immunofluorescence; the cGAS-STING-type I IFN pathway was evaluated by immunoblotting. Mitochondria functions were evaluated by electron microscope and seahorse equipment. <b>Results</b>: We have noted an increased expression of AGK in TAMs of multiple tumor types, which was negatively correlates with the tumor tissue immune scores. In the B16 and LLC tumor models, macrophage <i>Agk</i>-deficient mice have reduced tumor growth and enhanced populations of CD8⁺ Tpex. AGK-deficient macrophages have increased mitochondrial damage and mtDNA release into the cytosol, which leads to enhanced cGAS-STING-type I IFN activation. Blockade of the type I IFN signaling pathway with anti-IFNAR reversed the phenotype in <i>Agk</i>-deficient mice. <b>Conclusions</b>: Our findings define a critical role of AGK in maintaining the macrophage mitochondrial homeostasis that is associated with mtDNA release and following cGAS-STING activation and type I IFN pathway. Targeting AGK in TAMs may represent a novel strategy to enhance anti-tumoral activity.</p>","PeriodicalId":22932,"journal":{"name":"Theranostics","volume":"15 4","pages":"1304-1319"},"PeriodicalIF":12.4,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11729555/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143012086","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":"Development of dual aptamers-functionalized c-MET PROTAC degraders for targeted therapy of osteosarcoma.","authors":"Xuekun Fu, Jie Huang, Xinxin Chen, Duoli Xie, Hongzhen Chen, Zhijian Liang, Zhuqian Wang, Yiying Liang, Aiping Lu, Chao Liang","doi":"10.7150/thno.99588","DOIUrl":"10.7150/thno.99588","url":null,"abstract":"<p><p><b>Rationale:</b> Osteosarcoma (OS) is the most common bone malignancy. c-MET is recognized as a therapeutic target. However, traditional c-MET inhibitors show compromised efficacy due to the acquired resistance and side effects. PROTACs targeting c-MET have displayed improved antitumor efficacy by overcoming drug resistance, whereas safety concern caused by lack of tumor-targeting ability is still a pending issue. AS1411 is an aptamer that recognizes and penetrates tumors by targeting nucleolin (NCL) overexpressed on the surface of tumor cells. Since NCL interacts with an E3 ligase MDM2 intracellularly, we repurposed AS1411 as an MDM2 recruiter by employing NCL as a bridge. <b>Methods:</b> We select the ssDNA c-MET aptamer SL1 as the c-MET ligand to design dual aptamer-functionalized PROTACs, as SL1 can be easily conjugated to AS1411 through base-pair complementarity using a nucleic acid linker. Four AS1411-SL1 chimeras are generated by linking AS1411 to either the 5' or 3' terminus of SL1 via two different lengths of nucleic acid linkers. The therapeutic efficacy of these PROTACs is evaluated through both <i>in vitro</i> and <i>in vivo</i> experiments. <b>Results:</b> The PROTACs enable the ubiquitination and degradation of c-MET. The PROTACs effectively inhibit growth, enhance apoptosis, and overcome drug resistance of OS cells <i>in vitro</i>. The PROTACs demonstrate <i>in vivo</i> tumor-targeting ability and facilitate the OS treatment with no detectable toxicity. <b>Conclusion:</b> This study suggests that the AS1411-SL1 chimeras could be promising c-MET degraders for targeted therapy of OS.</p>","PeriodicalId":22932,"journal":{"name":"Theranostics","volume":"15 1","pages":"103-121"},"PeriodicalIF":12.4,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11667235/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142914823","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":"Integrating oxygen-boosted sonodynamic therapy and ferroptosis <i>via</i> engineered exosomes for effective cancer treatment.","authors":"Mingbo Wu, Zhanlin Zhang, Dong Li, Xiaomiao Ruan, Jingwen Yang, Siyi Chen, Xin Li, Wenwu Ling","doi":"10.7150/thno.102977","DOIUrl":"10.7150/thno.102977","url":null,"abstract":"<p><p><b>Rationale:</b> Ferroptosis and sonodynamic therapy (SDT) are both promising therapeutic modalities, but their clinical application remains challenging due to the hypoxic tumor microenvironment and limited supply of polyunsaturated fatty acids. Developing an agent with oxygen-enhanced SDT and increased ferroptosis sensitivity is crucial for advancing tumor therapy. <b>Methods:</b> In this study, catalase (Cat) and Acyl-CoA synthetase long-chain family member 4 (ACSL4) highly expressed 4T1 cells were constructed <i>via</i> lentivirus transfection. Cat and ACSL4 enriched exosomes (EXO@CA) were then extracted and loaded with the sonosensitizer tetrakis (4-carboxyphenyl) porphyrin (TCPP) through electroporation to create engineered exosomes (EXO@CAT). We evaluated the ability of EXO@CAT to generate oxygen in a hydrogen peroxide environment and investigated its effect on motion profiles and permeability of EXO@CAT. The <i>in vitro</i> antitumor activity was assessed <i>via</i> cytotoxicity, ROS levels, live/dead staining, and apoptosis, with ferroptosis biomarkers confirming ferroptosis activation. We also evaluated the <i>in vivo</i> anticancer efficacy of EXO@CAT by tumor growth analysis and histological and immunohistochemical staining in mouse models bearing breast tumor. <b>Results:</b> EXO@CAT harnesses ultrasound stimulation to facilitate oxygen-enriched SDT, demonstrating significant capacity for singlet oxygen (¹O₂) generating, which promotes the accumulation of lipid peroxidation (LPO), ultimately leading to the induction of ferroptosis. Concurrently, ACSL4 released from EXO@CAT also increases LPO accumulation by modifying cellular lipid composition, thereby enhancing cellular sensitivity to ferroptosis. Moreover, both <i>in vitro</i> and <i>in vivo</i> experiments demonstrate that the homologous targeting ability of EXO@CAT enables its efficient accumulation in tumor tissues, and the oxygen generation catalyzed by Cat not only alleviates tumor hypoxia but also facilitates the penetration of EXO@CAT into deeper layers of tumor tissue. <b>Conclusions:</b> EXO@CAT combines endogenous proteins, which are prone to inactivation, with an exogenous sonosensitizer, allowing synergistic anticancer treatment of both ferroptosis and SDT with improved efficacy.</p>","PeriodicalId":22932,"journal":{"name":"Theranostics","volume":"15 1","pages":"68-85"},"PeriodicalIF":12.4,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11667237/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142915091","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}