Theranostics最新文献

{"title":"Mn₃O₄ nanozyme-based anti-inflammatory therapy modulates microglial phenotype by downregulating TLR4/NOX2 expression and further alleviates Alzheimer's disease pathology.","authors":"Jun Xie, Kai Cao, Luman Liu, Liding Zhang, Ying Yang, Hui Gong, Haiming Luo","doi":"10.7150/thno.112213","DOIUrl":"10.7150/thno.112213","url":null,"abstract":"<p><p><b>Rationale:</b> Evidence shows that neuroinflammation mediated by microglial activation plays an important role in Alzheimer's disease (AD) pathogenesis. However, the relationship between microglial phenotype and fibrillar β-amyloid (fAβ) pathology in anti-inflammatory treatment of AD remains unclear. <b>Methods:</b> We designed a water-soluble Mn₃O₄ nanozymes and demonstrated its ability to reverse lipopolysaccharide (LPS)-induced microglial transition from M1 to M2 phenotype by clearing reactive oxygen species (ROS). <b>Results:</b> In 5×FAD transgenic mice, intranasal (IN) instillation of Mn₃O₄ nanozymes initially promoted M2 microglial polarization and significantly reduced neuroinflammation after 4 weeks of treatment. After 8 weeks of continuous treatment, they further alleviate fAβ pathology and improved learning and memory deficits in 5×FAD mice. The excellent anti-inflammatory effect of Mn₃O₄ nanozymes is achieved by inhibiting the Toll-like receptor 4 (TLR4)/nicotinamide adenine dinucleotide phosphate (NAPDH) oxidase isoform 2 (NOX2) pathway to clear ROS. <b>Conclusions:</b> This study reveals the molecular mechanism of Mn₃O₄ nanozymes modulating microglia phenotype to attenuate neuroinflammation primarily through inhibition of the TLR4/NOX2 pathway and highlights the temporal sequence of anti-inflammatory treatment in regulating microglial phenotype and improving fAβ pathology, providing new insights for the anti-inflammatory treatment of AD and other neurological diseases.</p>","PeriodicalId":22932,"journal":{"name":"Theranostics","volume":"15 15","pages":"7467-7488"},"PeriodicalIF":13.3,"publicationDate":"2025-06-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12315813/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144776212","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 α-synuclein and amylin co-aggregation: pathological insights and biomarker development for Parkinson's disease.","authors":"Yuhang Zhou, Minchao Lai, Bowen Shu, Benguo Wang, Dian Wang, Haoran Liu, Baowan Li, Jianhe Guo, Dongjie Hu, Mingyuan Li, Cheng Zhu, Muzhi Kang, Zhong Alan Li, Renzhi Wang, Yongjuan Zhao, Rocky S Tuan, Keying Guo, Chenzhong Li, Cheng Jiang","doi":"10.7150/thno.112396","DOIUrl":"10.7150/thno.112396","url":null,"abstract":"<p><p><b>Background:</b> Patients with diabetes have a higher morbidity in Parkinson's disease (PD) than others, but the mechanism underlying this link remains controversial. The co-aggregation of α-synuclein (α-syn) and amylin has been hypothesized as a key contributor. <b>Methods:</b> Molecular interaction analysis and co-immunoprecipitation were conducted to assess the feasibility of co-aggregation. We developed a tailored surface-based fluorescence distribution method to detect the co-aggregate in the subject's serum sample and brain-derived L1CAM-positive Extracellular Vesicles. Subjects include Health Controls (HC), PD patients and multiple system atrophy (MSA) patients. <b>Results:</b> The co-aggregates were detected in PD patient samples, in both serum and brain-derived extracellular vesicles (EVs). We demonstrated that the co-aggregate count could distinguish PD patients from healthy individuals. Our results revealed a positive correlation between co-aggregate count and Parkinson's disease scales or diabetes markers, highlighting the role of co-aggregation in promoting PD progression. The distribution of co-aggregates demonstrated diversity among different α-synucleinopathies; a high co-aggregates count was found in EVs and serum of PD patients, but not in the serum of MSA patients. <b>Conclusion:</b> The existence of α-syn-amylin co-aggregates was confirmed. Our findings suggest that α-syn-amylin co-aggregation may play a pivotal role in PD pathology, and have the potential as a biomarker. These results point to a potential path for early-diagnosis and therapeutic intervention.</p>","PeriodicalId":22932,"journal":{"name":"Theranostics","volume":"15 15","pages":"7409-7424"},"PeriodicalIF":13.3,"publicationDate":"2025-06-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12315819/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144776226","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":"Artemisiae Annuae Herba: from anti-malarial legacy to emerging anti-cancer potential.","authors":"Jing Sun, Junzi Xufeng, Zejing Qiu, Quan Gao, Zhiyu Zhu, Jun He, Shegan Gao, Xinbing Sui","doi":"10.7150/thno.115414","DOIUrl":"10.7150/thno.115414","url":null,"abstract":"<p><p>Modern medical approaches to cancer treatment face significant obstacles, including limited therapeutic options, narrow drug applicability, and rapid development of drug resistance. Consequently, re-evaluating traditional medicinal plants and natural compounds has emerged as a promising strategy to address this public health issue, particularly amid challenges in developing novel pharmaceuticals. Artemisiae Annuae Herba, a versatile natural drug renowned for its established efficacy against malaria and for other diverse pharmacological activities, is gaining recognition for its anti-cancer potential due to the unique structures and biological effects of its constituents. This review comprehensively outlines the major components of Artemisiae Annuae Herba and their reported anti-cancer activities, beginning with an examination of the molecular structures of the foundational components and an exploration of derivatives of these compounds. Furthermore, through an analysis of observed pharmacological effects, we systematically elucidate the multifaceted influence of Artemisiae Annuae Herba on cancerous tissues, including cell cycle arrest, apoptosis induction, non-apoptotic cell death induction, angiogenesis inhibition, tumor microenvironment remodeling, and immune modulation. Finally, we discuss the feasibility of Artemisiae Annuae Herba in cancer therapy as well as the challenges and unresolved issues that require further investigation. We also consider ways that new drug formulations and routes of administration might overcome these translational hurdles. By synthesizing existing research on applications of Artemisiae Annuae Herba to cancer therapy, this review underscores potentially innovative clinical approaches, ultimately paving the way for the discovery of effective anti-cancer drugs with far-reaching benefits.</p>","PeriodicalId":22932,"journal":{"name":"Theranostics","volume":"15 15","pages":"7346-7377"},"PeriodicalIF":13.3,"publicationDate":"2025-06-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12315818/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144776197","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 strain-programmed lignin-based Janus patch for rapid healing of postoperative rectal wounds.","authors":"Yi Yu, Jiaxin Pan, Jianbo Zhang, Zhengdong Zhang, Chenghao Qiu, Yiming Xiang, Yizhou Zhu, Zhanjun Wu, Peng Yu, Tong Li, Lei Tan","doi":"10.7150/thno.115444","DOIUrl":"10.7150/thno.115444","url":null,"abstract":"<p><p><b>Rationale:</b> Clinically, patients experience severe pain, frequent bleeding, and delayed wound healing after hemorrhoidectomy due to recurrent fecal contamination during postoperative dressing changes and bowel movements, which exacerbate wound irritation. <b>Methods</b>: In this study, we developed a strain-programmed lignin-based multifunctional Janus patch (S-SFR@AGL) to accelerate rectal wound repair. This patch features a pre-stretched fluorinated silicone rubber side with robust anti-biofouling and strain-programmed properties, paired with a lignin-based hydrogel side offering potent antibacterial, antioxidant, bioadhesive, and hemostatic capabilities. <b>Results</b>: By modulating the wound's mechanical microenvironment and combating infection-induced inflammation, the patch healed infected rat rectal wounds within one week via effective bacterial clearance, attenuated inflammatory responses, and promoted muscle contraction and epithelial cell differentiation. <b>Conclusions</b>: This Janus patch could shorten intestinal wound healing time, potentially optimizing postoperative management after intestinal lesion resection.</p>","PeriodicalId":22932,"journal":{"name":"Theranostics","volume":"15 15","pages":"7425-7439"},"PeriodicalIF":13.3,"publicationDate":"2025-06-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12315808/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144776195","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":"AI-powered 3D pathology protocol enhances enteric nervous system visualization and quantification for clinical diagnostics.","authors":"Young Hyun Yun, Kee Young Chung, Yunjoo Lee, Tae Sik Sung, Dayoung Ko, Seung-Bum Ryoo, Hyun-Young Kim, Kyu Joo Park, Jong Pil Im, Byeong Gwan Kim, Joo Sung Kim, Seong-Joon Koh, Hyung Jin Choi","doi":"10.7150/thno.112024","DOIUrl":"10.7150/thno.112024","url":null,"abstract":"<p><p><b>Rationale:</b> Accurate diagnosis and understanding of gastrointestinal (GI) diseases such as ulcerative colitis and Hirschsprung's disease remain challenging due to the limitations of traditional two-dimensional (2D) histopathology in capturing the intricate three-dimensional (3D) architecture and dynamic microenvironment of GI tissues. This study explores the potential of integrating 3D imaging techniques with artificial intelligence (AI)-based analysis to improve histological evaluation and diagnostic accuracy. <b>Methods:</b> Using advanced imaging and computational tools, we identified critical structural and functional details of the enteric nervous system and associated tissues that are often missed by 2D approaches. <b>Results:</b> The results showed that 3D imaging coupled with AI significantly improves diagnostic accuracy and provides new insights into disease mechanisms, enabling earlier and more precise detection of pathological changes. In addition, this approach enhances our understanding of the pathophysiology of GI diseases, bridging gaps in both clinical and basic research. <b>Conclusions:</b> These findings underscore the transformative potential of 3D imaging and AI to revolutionize diagnostic workflows and advance our knowledge of GI diseases, ultimately contributing to improved patient outcomes and innovative research methodologies.</p>","PeriodicalId":22932,"journal":{"name":"Theranostics","volume":"15 15","pages":"7440-7453"},"PeriodicalIF":13.3,"publicationDate":"2025-06-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12315810/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144776196","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":"Disrupted macrophage metabolic adaptation and function drive senescence-induced decline in vertebrate regeneration.","authors":"Audrey Barthelaix, Claudia Terraza-Aguirre, Yalén Del Río-Jay, Candice Bohaud, Jérémy Salvador, Marie Morille, Miguel Godinho Ferreira, Christian Jorgensen, Farida Djouad","doi":"10.7150/thno.111352","DOIUrl":"10.7150/thno.111352","url":null,"abstract":"<p><strong>Rationale: </strong>Senescent cells accumulate with age and contribute to impaired tissue regeneration. Here, we developed a senescence-accelerated zebrafish (SAZ) model, characterized by accelerated senescence-like traits and a significant impairment in caudal fin regeneration.</p><p><strong>Methods: </strong>To investigate the underlying mechanisms of this regenerative defect, we employed a multifaceted approach. We used transgenic zebrafish lines for 4-D tracking of macrophage subsets during regeneration and performed parabiosis to assess the impact of systemic factors. Then, we isolated macrophages by FACS-sorting for a comprehensive transcriptomic study using RT-qPCR, enabling us to analyze both senescence markers and metabolic markers specifically within SAZ macrophages. Furthermore, we conducted phagocytosis assays to evaluate macrophage function. To explore the role of specific metabolic pathways, we used pharmacological treatments with oligomycin and galloflavin.</p><p><strong>Results: </strong>Our findings revealed that the reduced regenerative potential in SAZ was partly attributable to an impaired macrophage response during regeneration. We observed higher expression of the senescence marker <i>cdkn2a/b</i> in SAZ macrophages, which correlated with their reduced ability to polarize into a pro-inflammatory phenotype and exert efficient phagocytosis. These observations were linked to a significant downregulation of <i>ldha</i>, a key enzyme in lactate production, specifically within SAZ macrophages at 24 hours post-amputation. Enhancing anaerobic glycolysis in the SAZ model during early regeneration restored <i>ldha</i> expression, normalized macrophage activation dynamics, and ultimately rescued caudal fin regeneration. This rescue was entirely abolished by co-treatment with galloflavin, a direct inhibitor of LDH isoforms A and B, thereby underscoring the critical role of lactate metabolism in the regenerative process.</p><p><strong>Conclusion: </strong>Collectively, our findings demonstrate that senescence impairs regeneration by altering macrophage metabolic adaptation and functions, providing novel insights into the interplay between aging and regenerative capacity.</p>","PeriodicalId":22932,"journal":{"name":"Theranostics","volume":"15 15","pages":"7308-7326"},"PeriodicalIF":13.3,"publicationDate":"2025-06-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12315812/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144776200","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":"Comparison of targeting two antigens (GPA33 versus HER2) for ²²⁵Ac-pretargeted alpha-radioimmunotherapy of colorectal cancer.","authors":"Sara S Rinne, Daniela Burnes Vargas, Brett A Vaughn, Sumudu Katugampola, Brian W Miller, Darren R Veach, Blesida Punzalan, Elisa de Stanchina, Rona Yaeger, Ileana C Miranda, Hong Xu, Hongfen Guo, Jazmin Schwartz, Edward K Fung, Roger W Howell, Steven M Larson, Nai-Kong V Cheung, Sarah M Cheal","doi":"10.7150/thno.116062","DOIUrl":"10.7150/thno.116062","url":null,"abstract":"<p><p><b>Purpose:</b> Curative therapies remain a significant unmet need for advanced human colorectal cancer (CRC). The aim of this study was to establish a 3-step ²²⁵Ac-DOTA pretargeted radioimmunotherapy (PRIT) system for human CRC, targeting two individual antigens: glycoprotein A33 (GPA33) and human epidermal growth factor receptor 2 (HER2). <b>Methods:</b> <i>In vitro</i> cellular uptake and internalization assays, as well as survival assays (colony forming) were performed in GPA33- and HER2-positive SW1222 human CRC cells. <i>In vivo</i> biodistribution and therapy studies were performed with two human CRC xenograft mouse models. <b>Results:</b> For both antigens, treatment with up to 74 kBq ²²⁵Ac-DOTA-PRIT in SW1222-tumored mice significantly enhanced overall survival in comparison to controls, including histologic cures. The uptake of ²²⁵Ac at the tumor correlated with antigen expression (antigen expression for GPA33:HER2 is 5:1). Cellular assays showed no significant differences in internalized fraction or nucleus-associated radioactivity between the two targets. GPA33 had a higher absorbed dose to the nucleus (1.3 Gy <i>vs.</i> 0.65 Gy for HER2), resulting in reduced clonogenic survival. A single cycle of either GPA33 or HER2 DOTA-PRIT (37 kBq; 193.31 Gy and 113.91 Gy (relative biological effectiveness [RBE] = 5), respectively) was equally effective. No chronic nephrotoxicity was seen at ≤ 20 Gy (RBE = 5). The efficacy of GPA33-directed ²²⁵Ac-DOTA-PRIT was also confirmed in a patient-derived xenograft model. <b>Conclusion:</b> In summary, ²²⁵Ac-DOTA-PRIT to GPA33 or HER2 was highly effective and safe in preclinical models of human CRC. Tumor response to treatment could not be predicted by nuclear absorbed dose alone, highlighting the importance of comprehensive micro- and macro-dosimetry.</p>","PeriodicalId":22932,"journal":{"name":"Theranostics","volume":"15 15","pages":"7489-7500"},"PeriodicalIF":13.3,"publicationDate":"2025-06-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12315807/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144776199","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":"Focusing on the interplay between tumor-associated macrophages and tumor microenvironment: from mechanism to intervention.","authors":"Hancheng Wu, Jing Li, Ruilin Yao, Jing Liu, Lili Su, Wenjie You","doi":"10.7150/thno.113727","DOIUrl":"10.7150/thno.113727","url":null,"abstract":"<p><p>Immunotherapy has generated promising outcomes in cancer treatment; however, therapeutic responses are hampered by immunosuppression in the tumor microenvironment (TME). This has resulted in increased study of key immune cells in the TME as therapeutic interventions. Tumor-associated macrophages (TAMs), a major component of infiltrating immune cells in the TME, display high plasticity, largely dependent on cues received from their surroundings. Although significant progress in metabolomics and single-cell omics has unraveled the metabolic and functional heterogeneity of TAMs across several types of cancer, the development of TAM-targeted therapy remains challenging. In the present review, the crosstalk between TAMs and other components in TME, such as tumor cells, immune cells, cancer-associated fibroblasts, and extracellular matrix is highlighted. Additionally, updated insights into the origin, heterogeneity, and metabolic reprogramming of TAMs are discussed, and relevant approaches of targeting TAMs in clinical investigations are summarized. The present review provides a deeper understanding of TAMs within the microenvironment network, aimed at identifying candidate targets to improve cancer immunotherapy.</p>","PeriodicalId":22932,"journal":{"name":"Theranostics","volume":"15 15","pages":"7378-7408"},"PeriodicalIF":13.3,"publicationDate":"2025-06-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12315823/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144776204","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":"Neutrophil extracellular traps aggravate neuronal apoptosis and neuroinflammation via neddylation after traumatic brain injury.","authors":"Xu Zhang, Jianye Xu, Yonggang Fan, Guihong Shi, Bo Chen, Anni Wang, Yanlin Zhu, Lei Li, Haoran Jia, Dilmurat Gheyret, Jinchao Wang, Yiyao Cao, Shenghui Li, Xin Chen, Jianning Zhang, Shu Zhang","doi":"10.7150/thno.111512","DOIUrl":"10.7150/thno.111512","url":null,"abstract":"<p><p><b>Rationale:</b> Neddylation, akin to ubiquitination, regulates various cellular processes by attaching neuronal precursor cell-expressed developmentally down-regulated protein 8 (NEDD8) to target proteins. Its specific role in traumatic brain injury (TBI) remains poorly defined. Neutrophil extracellular traps (NETs), which accumulate at injury sites in TBI models, are linked to poor outcomes, yet the connection between NETs and neddylation remains unclear. <b>Methods:</b> We analyzed contused brain tissues from TBI patients and mice subjected to controlled cortical impact (CCI) using Western blotting, immunofluorescence, and immunohistochemistry. Neddylation was inhibited using MLN4924, a small-molecule NEDD8-activating enzyme (NAE) inhibitor. We conducted short-term neurobehavioral tests, Fluoro-Jade C staining, TUNEL assay, and Evans blue extravasation. Additionally, co-immunoprecipitation (Co-IP) and mass spectrometry were employed to explore the mechanisms of neddylation post-TBI. <b>Results:</b> Neddylation increased in neurons during the acute phase of TBI. Inhibition of neddylation with MLN4924 reduced neuronal death, mitigated proinflammatory polarization of microglia, and maintained the integrity of the blood-brain barrier (BBB). MLN4924 treatment also decreased cerebral lesion volume and improved short-term neurological outcomes. NETs induced neuronal neddylation and apoptosis, while MLN4924 rescued neurons from NET-induced apoptosis. Mechanistically, NETs promoted NEDD8 binding to the ubiquitin ligase TRIM56, facilitating STING K63-linked ubiquitination and activating the NF-kB pathway, leading to neuroinflammation and neuronal death. <b>Conclusions:</b> Our study revealed that NETs trigger neuronal death and neuroinflammation via neddylation. We propose that inhibiting neddylation could offer therapeutic benefits in TBI.</p>","PeriodicalId":22932,"journal":{"name":"Theranostics","volume":"15 15","pages":"7327-7345"},"PeriodicalIF":13.3,"publicationDate":"2025-06-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12315821/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144776214","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":"Autophagy inhibitor-sensitized artificially activated neutrophils against hepatocellular carcinoma.","authors":"Caixia Yang, Huang Yang, Zhengwei Mao, Weilin Wang, Yuan Ding","doi":"10.7150/thno.106404","DOIUrl":"10.7150/thno.106404","url":null,"abstract":"<p><p>The use of activated neutrophils has emerged as a promising antineoplastic method in oncology. However, challenges, including a short lifespan, susceptibility to the tumor microenvironment, and protumorigenic risks, limit their clinical application. While artificial neutrophils have several limitations, few tumor-related studies have been conducted with constraining factors, including specific targeting inefficiency, immunogenicity and manufacturing challenges. Neutrophil elastase (ELANE), a key antitumor effector in activated neutrophils, is functionally mimicked by porcine pancreatic elastase (PPE), which exhibits selective cancer cytotoxicity. However, PPE triggers protective autophagy in hepatocellular carcinoma (HCC), limiting its therapeutic effectiveness. <b>Methods</b>: To overcome this resistance, we sensitized PPE by the autophagy inhibitor 3-methyladenine (3MA), which is codelivered via tumor-targeting liposomes. This system protects drugs and improves therapeutic efficacy both <i>in vitro</i> and <i>in vivo</i>. <b>Results</b>: 3MA enhanced iron-related ROS-mediated cell destruction induced by PPE while suppressing prosurvival autophagy. The autophagy inhibitor-sensitized artificially activated neutrophils (asAN-P/3) showed precise tumor targeting, excellent therapeutic efficacy, prolonged survival and favorable biocompatibility. <b>Conclusions</b>: We established a precise neutrophil-related tumor therapeutic method (asAN-P/3) and elucidated the mechanistic insights into PPE-mediated therapeutic limitations in HCC. Our study provides a substantial framework for the development of neutrophil-derived antitumor therapeutic strategies in oncology.</p>","PeriodicalId":22932,"journal":{"name":"Theranostics","volume":"15 14","pages":"7197-7218"},"PeriodicalIF":12.4,"publicationDate":"2025-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12204081/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144529553","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}