Journal of Controlled Release最新文献

{"title":"Nanoparticle-based methionine and AICAR delivery elicits a robust antitumor immune response","authors":"Ye Gu ,&nbsp;Bao Loc Nguyen ,&nbsp;Sunil Mishra,&nbsp;Ram Hari Pokhrel,&nbsp;Manoj Sharma,&nbsp;Mahesh Pandit,&nbsp;Le Minh Pham,&nbsp;Basavaraj Patil,&nbsp;Jeonghwan Kim,&nbsp;Jong Oh Kim,&nbsp;Jae-Hoon Chang","doi":"10.1016/j.jconrel.2025.113981","DOIUrl":"10.1016/j.jconrel.2025.113981","url":null,"abstract":"<div><div>Immunotherapy uses the immune system's intrinsic defense mechanisms to destroy malignancies and has garnered increasing interest in recent years. The main objectives of immunotherapy are activating immune cells and forming a strong antitumor immune response. The tumor microenvironment (TME) is a complex ecology full of chemicals that can substantially affect immune cell activity, especially the function of CD4⁺ T cells. In this study, we produced an artificial nanoparticle (NP) comprising methionine and AICAR with PD-1 antibodies attached to its surface, targeted at increasing effector immune responses by directly altering the TME. By targeting PD-1 receptors, this coloaded NP effectively travels to the tumor site and activates CD4⁺ T cells within the TME. After receiving these NPs, the mice's tumor-infiltrating CD4⁺ T cells expressed less PD-1, and their Th1-driven antitumor immunity increased. These effects resulted in substantial tumor inhibition. Our findings suggest that this NP-based technique, which direct regulates the TME, has the potential as a robust tool to enhance anticancer efficacy by promoting immune cell activation within the TME.</div></div>","PeriodicalId":15450,"journal":{"name":"Journal of Controlled Release","volume":"385 ","pages":"Article 113981"},"PeriodicalIF":10.5,"publicationDate":"2025-06-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144371032","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Camel milk extracellular vesicles-mediated co-delivery of siVEGF/sorafenib enhances the anti-hepatocellular carcinoma activity by dual-effect blocking the biological effects of VEGF","authors":"Feng Chen ,&nbsp;Yichen Pan ,&nbsp;Zhou Fang ,&nbsp;Mengdi Song ,&nbsp;Wang Zhang ,&nbsp;Hui Yuan ,&nbsp;Xinran Gao ,&nbsp;Min Zhang ,&nbsp;Kehai Liu","doi":"10.1016/j.jconrel.2025.113980","DOIUrl":"10.1016/j.jconrel.2025.113980","url":null,"abstract":"<div><div>In view of the combined effect of paracrine and autocrine of VEGF in tumor tissues, this study proposed to use <em>sorafenib</em> to block VEGF signaling pathway, while siRNA was used to interfere with tumor cell autocrine of VEGF, so as to achieve double-effect blocking of VEGF biological effects and further improve anti-tumor efficacy. Here, we constructed a novel co-delivery system (<em>so</em>-cEVs-PPT/siVEGF) based on camel milk-derived extracellular vesicles (cEVs) modified by Plannic 123-polyethylenimine-tLyP-1 transmembrane peptide polymer (PPT) for the delivery of siVEGF and <em>sorafenib</em>. The results showed that <em>so</em>-cEVs-PPT/siVEGF exhibited significant tumor inhibition and low side effects on hepatocellular carcinoma mice, and the combined administration system had stronger anti-tumor effects than siVEGF or <em>sorafenib</em> alone. More importantly, the two different delivery modes of intravenous injection and intratumoral injection showed comparable anti-tumor therapeutic effects, which proved that the drug delivery system had superior targeted therapeutic effects. This study proposes an innovative combination therapy strategy that provides new perspectives and possibilities for the treatment of hepatocellular carcinoma.</div></div>","PeriodicalId":15450,"journal":{"name":"Journal of Controlled Release","volume":"385 ","pages":"Article 113980"},"PeriodicalIF":10.5,"publicationDate":"2025-06-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144371033","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Transdermal hyaluronate/cationic solid lipid nanoparticle/siRNA complex for the treatment of skin cancer","authors":"Zhengyu Piao,&nbsp;Mungu Kim,&nbsp;Jin Huh,&nbsp;Sei Kwang Hahn","doi":"10.1016/j.jconrel.2025.113967","DOIUrl":"10.1016/j.jconrel.2025.113967","url":null,"abstract":"<div><div>Lipid nanoparticles (LNPs) are widely recognized for their potential in drug delivery. However, they exhibit significant limitations in stability and targeting. In this study, we designed a target-specific siRNA delivery system by coating hyaluronate (HA) onto cationic solid lipid nanoparticles (CSLNs). The angiogenesis-inhibiting siVEGF formed a stable nanoscale complex for the targeted delivery to skin cancer tissue. The nucleic acid drug in the HA/CSLN/siVEGF complex was electrostatically coated on the surface of CSLN, enabling high drug loading capacity. Moreover, HA appeared to serve a dual purpose in this design by targeting to cancer cells and facilitating effective transdermal delivery. The optimized HA/CSLN/siVEGF complex resulted in facilitated transdermal delivery, effective tumor targeting, and significantly reduced VEGF mRNA levels, leading to tumor growth inhibition. Taken together, the HA/CSLN complex would be successfully harnessed as a transdermal target-specific delivery carrier of siRNA for cancer therapy.</div></div>","PeriodicalId":15450,"journal":{"name":"Journal of Controlled Release","volume":"385 ","pages":"Article 113967"},"PeriodicalIF":10.5,"publicationDate":"2025-06-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144371035","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"In situ construction of ossification micro-units for critical bone regeneration via sustained lifting of epigenetic suppression","authors":"Wu Yang ,&nbsp;Tao Ding ,&nbsp;Pengzhen Zhuang ,&nbsp;Yu Chen ,&nbsp;Yu Zhang ,&nbsp;Zehao Chen ,&nbsp;Minjie Fan ,&nbsp;Tapani Viitala ,&nbsp;Zhongmin Wang ,&nbsp;Wenguo Cui ,&nbsp;Hongbo Zhang","doi":"10.1016/j.jconrel.2025.113978","DOIUrl":"10.1016/j.jconrel.2025.113978","url":null,"abstract":"<div><div>Critical-sized bone defects present significant clinical challenges due to insufficient stem cell recruitment, epigenetic suppression of osteogenesis, and inadequate mineralization. Among the epigenetic suppression mechanisms, upregulated MEG3 specifically recruits the epigenetic regulator EZH2 to block the transcription of β-catenin, a core gene for bone regeneration. To regulate MEG3 <em>in vivo</em> effectively, we used microfluidics to develop <em>in situ</em> continuous MEG3-silencing ossification micro-units (MSOMs) that integrate “material–gene–biofactor” tri-coupling into a unified biomaterial system. The MSOMs are nano-micro particles composed of amorphous calcium phosphate nanoparticles loaded with siRNA (si@BCP) in GelMA microgels loaded with stromal cell-derived factor-1α (SDF-1α). The SDF-1α in the microgel layer is rapidly released to recruit BMSCs, while the siRNA in si@BCP has sustained release to silence MEG3 and restore β-catenin transcription continuously. Thus, the MSOMs provide a stable mineralization microenvironment for ossification center formation. <em>In vivo</em> observations revealed the formation of ossification centers around these micro-units, tripling new bone formation and achieving efficient bone regeneration. By addressing the key limitations of traditional therapies, MSOMs offer a clinically viable solution that integrates stem cell recruitment, epigenetic regulation, and biomaterial-based mineralization, thus providing a highly efficient approach for critical bone defect repair.</div></div>","PeriodicalId":15450,"journal":{"name":"Journal of Controlled Release","volume":"385 ","pages":"Article 113978"},"PeriodicalIF":10.5,"publicationDate":"2025-06-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144371034","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Nucleic acid-based nanogels with “offensive and defensive”effects for enhanced chemo-immunotherapy","authors":"Zijian Zhao ,&nbsp;Fei Sun ,&nbsp;Wenyu Wang ,&nbsp;Bing Li ,&nbsp;Yan Liang ,&nbsp;Dengshuai Wei ,&nbsp;Yong Sun ,&nbsp;Jianqin Yan","doi":"10.1016/j.jconrel.2025.113977","DOIUrl":"10.1016/j.jconrel.2025.113977","url":null,"abstract":"<div><div>Chemotherapeutic drugs such as doxorubicin (DOX) can activate CD8⁺ T cell-mediated antitumor immune responses by inducing immunogenic cell death (ICD), demonstrating the potential of chemo-immune synergistic therapy. However, the continuous stimulation of tumor antigens triggers the exhaustion of CD8⁺ T cells, which has become the main obstacle to inhibiting tumor growth and metastasis. Dual regulation of T cell infiltration and exhaustion to elicit a robust immune response is the key for optimizing tumor immunotherapy. In this study, a membrane-coated framework nucleic acid-based nanogel (RM@NG/DOX) was developed to co-deliver DOX and siRNA (siTOX, thymocyte selection-associated high mobility group box protein, TOX) for the spatiotemporal synergistic regulation of chemo-immunotherapy. This system broke the traditional cationic carrier mode of siRNA delivery and constructed a double-layer barrier to further protect the loaded siTOX and DOX. RM@NG/DOX induced ICD by DOX as an “offensive” signal to enhance T cell infiltration, while siTOX as a “defensive module” reversed the differentiation of exhausted T cells (PD-1⁺ Tim-3⁺) by silencing TOX, a key regulator of T cell exhaustion. Experiments <em>in vitro</em> and <em>in vivo</em> confirmed that RM@NG/DOX reshaped the immune microenvironment through the dual pathway of “activation-reversal” to effectively inhibit tumor growth and metastasis, successfully transforming the “cold tumor” into an immune-infiltrated “hot tumor” and enhancing chemo-immunotherapy. In summary, the combined chemo-genetic nanomedicine based on nucleic acid nanogels provides a new strategy for chemo-immunotherapy and the regulation of T cell exhaustion.</div></div>","PeriodicalId":15450,"journal":{"name":"Journal of Controlled Release","volume":"385 ","pages":"Article 113977"},"PeriodicalIF":10.5,"publicationDate":"2025-06-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144334842","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Homotypic biomimetic nanotheranostics enhance locoregional Cherenkov radiation-induced photodynamic therapy and ferroptosis in early bone metastases","authors":"Rui Xue ,&nbsp;Shuai Li ,&nbsp;Fengyu Wang ,&nbsp;Xiaojing Zou ,&nbsp;Beibei Zhang ,&nbsp;Chunshui Yu ,&nbsp;Qiusong Chen ,&nbsp;Jin Wu ,&nbsp;Chunyang Sun","doi":"10.1016/j.jconrel.2025.113971","DOIUrl":"10.1016/j.jconrel.2025.113971","url":null,"abstract":"<div><div>Theranostics for deep-seated and multifocal bone metastases using conventional nanoparticulate strategies face significant challenges due to limited targeting and insufficient spatial controllability within the lesions. Here, we developed a sophisticated nanocarrier (MC@MH) camouflaged with the homologous prostate cancer cell membrane and ferritin-homing peptide (HKN₂₂). Following systemic injection, the biomimetic nanotheranostics preferentially accumulated in bone metastases through a homotypic targeting mechanism. The acidic/H₂O₂-rich microenvironment triggered the degradation of MnO₂ in MC@MH, leading to the release of Mn²⁺ ions that enhance magnetic resonance imaging (MRI) for bone metastases, particularly at early stages. The HKN₂₂ further promoted interactions between MC@MH and intracellular ferritin. Guided by MRI, the separately administrated radionuclide (⁶⁸Ga-PSMA-617) also actively navigated to metastatic tumors. Based on the Cherenkov radiation effect, it served as a light source in the lesions, precisely irradiating the photosensitizer (Chlorin e6) released from MC@MH. The cytotoxic ROS generated from Cherenkov radiation-induced PDT not only destroyed cancer cells but also destructed ferritin to initiate a cascade of ferroptosis. Overall, our strategy facilitated bone remodeling and repair while preserving bone homeostasis, offering a novel avenue for locoregional and precise theranostics against metastatic cancer <em>in vivo</em>.</div></div>","PeriodicalId":15450,"journal":{"name":"Journal of Controlled Release","volume":"385 ","pages":"Article 113971"},"PeriodicalIF":10.5,"publicationDate":"2025-06-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144329177","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"High-resolution imaging reveals a cascade of interconnected cellular bioeffects differentiating the long-term fates of sonoporated cells","authors":"Jonathan L.F. Lee ,&nbsp;Jae Song ,&nbsp;Rumelo Amor ,&nbsp;Jonathon Bolton ,&nbsp;Andrew Thompson ,&nbsp;Jürgen Götz ,&nbsp;Pranesh Padmanabhan","doi":"10.1016/j.jconrel.2025.113974","DOIUrl":"10.1016/j.jconrel.2025.113974","url":null,"abstract":"<div><div>Low-intensity ultrasound combined with microbubbles is a promising, non-invasive treatment strategy for enhancing vascular permeability and targeted intracellular drug or gene delivery. Following ultrasound insonification, cells can undergo reversible sonoporation, involving adaptation and recovery, or irreversible sonoporation, marked by a loss of cell viability. To design effective sonoporation-based therapeutic delivery strategies, it is critical to identify the biological responses that determine these distinct cell fates. Here, we developed a custom-built high-resolution multicolour imaging device and applied a single pulse of ultrasound (267 kHz frequency, 20 μs duration, and ∼110 kPa peak negative pressure) to trigger targeted microbubble-mediated reversible and irreversible sonoporation events within a confluent monolayer of cultured Madin-Darby canine kidney (MDCK) II cells. We found that intracellular calcium levels rose rapidly and peaked within 10 s in both types of sonoporated cells, although the levels declined differently. In reversibly sonoporated cells, these levels gradually returned to baseline, whereas in irreversibly sonoporated cells, they dropped rapidly, falling well below baseline within 7.9 ± 3.0 min (mean ± s.d.). Using single-vesicle imaging, we further found that vesicles containing the tight junction protein claudin-5 remained mobile with subtly reduced movement in reversibly sonoporated cells, whereas they almost stalled in irreversibly sonoporated cells. The underlying microtubule network was partially disrupted in the reversibly sonoporated cells, recovering fully within 3.2 ± 2.9 min (mean ± s.d.). In contrast, in irreversibly sonoporated cells, the entire microtubule network collapsed within 4.0 ± 2.4 min (mean ± s.d.). Whilst in reversibly sonoporated cells, the uptake of the model drug propidium iodide was mild-to-moderate, without drastic cell size changes up to about 1 h post-sonication, irreversibly sonoporated cells presented with substantially higher propidium iodide uptake and completely shrank within 43.2 ± 10.5 min (mean ± s.d.). Together, our study identified distinct spatiotemporal sequences of interconnected biological responses underlying the different fates of sonoporated cells, providing a framework for identifying processes that could be manipulated for safe and effective sonoporation-based drug delivery.</div></div>","PeriodicalId":15450,"journal":{"name":"Journal of Controlled Release","volume":"385 ","pages":"Article 113974"},"PeriodicalIF":10.5,"publicationDate":"2025-06-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144334843","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Nano-golden adjuvant-polymersomes empower tumor photothermal-immunotherapy","authors":"Zhiwei Sun ,&nbsp;Jingyi Wang ,&nbsp;Beibei Guo ,&nbsp;Songsong Zhao ,&nbsp;Shiyu Miao ,&nbsp;Mingyu Xia ,&nbsp;Zhiyuan Zhong ,&nbsp;Fenghua Meng","doi":"10.1016/j.jconrel.2025.113976","DOIUrl":"10.1016/j.jconrel.2025.113976","url":null,"abstract":"<div><div>The integration of photothermal therapy with immunotherapy represent a potential treatment for tumor patients. Here, we demonstrate that nano‑golden adjuvant-polymersomes (nGAP) with gold nanoclusters imbedded in the membrane and immunoadjuvant poly(I:C) encapsulated within the aqueous core empower tumor photothermal-immunotherapy. Upon near-infrared irradiation, nGAP elicits a strong photothermal effect on tumor cells, driving immunogenic cell death and activating dendritic cells. In murine LLC lung tumor models, a single session of irradiation following intratumoral injection of nGAP led to an impressive 83% cure rate, which further increased to 100% complete regression by equipping cRGD peptide on the polymersome surface and combining with anti-CTLA-4 antibody. Furthermore, the cured mice exhibited effective resistance to subsequent tumor re-challenges. Our findings also reveal that nGAP yields explicit abscopal effects, supporting the development of systemic and long-lasting anticancer immunity. nGAP presents an interesting therapeutic modality capable of effectively ablating both primary solid tumors and their metastatic counterparts.</div></div>","PeriodicalId":15450,"journal":{"name":"Journal of Controlled Release","volume":"385 ","pages":"Article 113976"},"PeriodicalIF":10.5,"publicationDate":"2025-06-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144334841","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mitochondria-targeted NAD+/O2 co-delivery interpenetrating network hydrogel for respiratory chain restoration and osteoarthritis therapy","authors":"Xiaolong Shen ,&nbsp;Jinquan Hu ,&nbsp;Chen Wang ,&nbsp;Haoyi Wang ,&nbsp;Huajian Zhong ,&nbsp;Zifan Zhang ,&nbsp;Guoqing Wen ,&nbsp;Lei Wang ,&nbsp;Minjie Dong ,&nbsp;Ye Tian","doi":"10.1016/j.jconrel.2025.113975","DOIUrl":"10.1016/j.jconrel.2025.113975","url":null,"abstract":"<div><div>Mitochondrial respiratory chain dysfunction-induced chondrocyte senescence is a key contributor to the progression of osteoarthritis (OA), yet effective strategies for restoring mitochondrial respiratory homeostasis remain elusive. Herein, we develop a charge-guided micro/nano interpenetrating network hydrogel that targets cartilage and delivers a mitochondria-directed MnO₂-based nanoparticles, in which the nanozyme catalyzes intracellular hydrogen peroxide to generate oxygen while releasing nicotinamide adenine dinucleotide (NAD⁺) precursor via particle degradation, thereby enabling synchronized electron donor and acceptor supply to fully reactivate the mitochondrial respiratory chain and alleviate chondrocyte senescence. Comprehensive evaluations reveal that this system enhances the activity of key antioxidant enzymes including superoxide dismutase, catalase, and glutathione peroxidase, elevates the intracellular nicotinamide adenine dinucleotide/nicotinamide adenine dinucleotide hydrogen (NAD⁺/NADH) ratio, and suppresses the secretion of senescence-associated secretory phenotype factors, thereby preserving cartilage matrix integrity. Collectively, these findings underscore the therapeutic potential of this dual-delivery platform to achieve full-length mitochondrial respiratory chain activation, offering a compelling strategy to mitigate chondrocyte senescence and impede OA progression.</div></div>","PeriodicalId":15450,"journal":{"name":"Journal of Controlled Release","volume":"385 ","pages":"Article 113975"},"PeriodicalIF":10.5,"publicationDate":"2025-06-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144335059","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Engineered bacterial extracellular vesicles for gastrointestinal diseases","authors":"Xinke Nie ,&nbsp;Qiqiong Li ,&nbsp;Ying He ,&nbsp;Yushan Xu ,&nbsp;Shanfeng Qiao ,&nbsp;Xingdong Wang ,&nbsp;Fan Meng ,&nbsp;Junhua Xie ,&nbsp;Shaoping Nie","doi":"10.1016/j.jconrel.2025.113972","DOIUrl":"10.1016/j.jconrel.2025.113972","url":null,"abstract":"<div><div>The gut microbiota, a complex microbial ecosystem within the gastrointestinal (GI) tract, plays a pivotal role in maintaining GI homeostasis. Dysbiosis of this community is increasingly implicated in the pathogenesis of diverse GI disorders. Bacterial extracellular vesicles (bEVs) secreted from gut microbes have emerged as an innovative therapeutic nanoplatform for GI diseases. Their unique advantages, including intrinsic biocompatibility, low immunogenicity, high drug-loading capacity, ease of customization and scalability make them a promising candidate for next-generation nanotherapies. In this review, we first discuss the biogenesis pathways, composition and internalization mechanisms of bEVs, with a particular focused on the bioactivities and mechanisms of natural bEVs in modulating gut health. Additionally, we highlight different bEVs engineering approaches to enhance bEVs functionality, stability, and disease-specific targeting, offering insights applicable to GI therapy and beyond. Despite the great potential of bEVs in various biomedical applications, challenges remain in developing standardized, scalable and reproducible bEVs production methods to facilitate clinical translation. Addressing these barriers is critical to unlocking the full therapeutic potential of bEVs in the GI disorders and other biomedical applications.</div></div>","PeriodicalId":15450,"journal":{"name":"Journal of Controlled Release","volume":"385 ","pages":"Article 113972"},"PeriodicalIF":10.5,"publicationDate":"2025-06-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144319608","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}