Journal of Controlled Release最新文献

{"title":"Enhancing immunogenicity and release of in situ-generated tumor vesicles for autologous vaccines","authors":"Jin-hu Chen ,&nbsp;Cai-li Zhao ,&nbsp;Jing Zhang ,&nbsp;Jia-wen Cheng ,&nbsp;Jian-ping Hu ,&nbsp;Pei Yu ,&nbsp;Ming-hua Yang ,&nbsp;Yuan-zheng Xia ,&nbsp;Yong Yin ,&nbsp;Zhen-zhen Zhang ,&nbsp;Jian-guang Luo ,&nbsp;Ling-yi Kong ,&nbsp;Chao Zhang","doi":"10.1016/j.jconrel.2025.113614","DOIUrl":"10.1016/j.jconrel.2025.113614","url":null,"abstract":"<div><div><em>In situ</em> vaccination (ISV) strategies offer an innovative approach to cancer immunotherapy by utilizing drug combinations directly at tumor sites to elicit personalized immune responses. Tumor cell-derived extracellular vesicles (TEVs) in ISV have great potential but face challenges such as low release rates and immunosuppressive proteins like programmed death ligand 1 (PD-L1) and CD47. This study develops a nanoparticle-based ISV strategy (Combo-NPs@shGNE) that enhances TEV release and modulates cargo composition. This approach combines Andrographolide, Icariside II, and shRNA targeting UDP-<em>N</em>-acetylglucosamine 2-epimerase/<em>N</em>-acetylmannosamine kinase (GNE), which accumulates in the tumor region, resulting in the regulation of immunosuppressive pathways and the reduction of sialic acid production. Decreasing the level of sialylation on the membrane through necroptosis and inhibition of sialic acid synthesis decreased the loading of PD-L1 and CD47 on vesicles, while increasing the loading of heat shock protein 70 and high mobility group box 1 on vesicles, and induced the release of highly immunogenic TEVs from the cancer cells, with a 56.44 % release, 9.57 times higher than that of blank nanoparticle-treated cells. <em>In vivo</em> studies demonstrate that Combo-NPs@shGNE enhances TEV yield, tumor growth, reduces metastases, and improves survival in an osteosarcoma mouse model. It promotes dendritic cell maturation, increases CD4⁺ and CD8⁺ T cell infiltration, and alters the microenvironment by reducing myeloid-derived suppressor cells and enhancing immunostimulatory factors. Additionally, it transitions tumor-associated macrophages from M2 to an M1 phenotype, thereby augmenting tumor immunity. Overall, Combo-NPs@shGNE offers a promising method for transforming tumors into personalized autologous vaccines, potentially advancing cancer treatment strategies.</div></div>","PeriodicalId":15450,"journal":{"name":"Journal of Controlled Release","volume":"381 ","pages":"Article 113614"},"PeriodicalIF":10.5,"publicationDate":"2025-03-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143576201","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":"Exosomal delivery of rapamycin modulates blood-brain barrier penetration and VEGF axis in glioblastoma","authors":"Lin Lin Song ,&nbsp;Yong Pei Tang ,&nbsp;Yuan Qing Qu ,&nbsp;Yun Xiao Yun ,&nbsp;Rui Long Zhang ,&nbsp;Cai Ren Wang ,&nbsp;Vincent Kam Wai Wong ,&nbsp;Hui Miao Wang ,&nbsp;Meng Han Liu ,&nbsp;Li Qun Qu ,&nbsp;Jian Hui Wu ,&nbsp;Hang Hong Lo ,&nbsp;Betty Yuen Kwan Law","doi":"10.1016/j.jconrel.2025.113605","DOIUrl":"10.1016/j.jconrel.2025.113605","url":null,"abstract":"<div><div>Exosomes (Exos), nanosized membranous vesicles (30–160 nm), have been validated as an effective drug delivery system capable of traversing biological barriers. Mesenchymal stem cells (MSCs), due to their near-limitless self-renewal capabilities, provide a plentiful source of exosomes for clinical applications. In this study, we utilized an exosome-encapsulated rapamycin (Exo-Rapa) delivery strategy, which permits the use of smaller drug dosages to achieve effects typically seen with higher dosages, thus enhancing drug efficacy. Moreover, Exos can transport pharmaceuticals across the blood-brain barrier (BBB) to the brain, and further penetrate GL261 cells to exert their effects. Within the tumor microenvironment, Exo-Rapa is released more rapidly and efficiently at the tumor site. The acidic conditions in tumors accelerate the release of Exo-Rapa, a characteristic that may make it a promising targeted therapeutic in future cancer research. Additionally, a series of <em>in vivo</em> experiments have further demonstrated the permeability of Exo-Rapa across the BBB, enabling it to accumulate at tumor sites; it also ameliorates inflammatory responses in Glioblastoma multiforme (GBM) mouse models and enhances anti-tumor activity through the regulation of angiogenesis via the VEGF/VEGFRs axis. Our results indicate that MSC-derived exosomes are a potent therapeutic carrier for GBM, offering an effective strategy for enhancing drug delivery across the BBB and providing a scientific foundation for the use of exosomes in the treatment of GBM and other diseases.</div></div>","PeriodicalId":15450,"journal":{"name":"Journal of Controlled Release","volume":"381 ","pages":"Article 113605"},"PeriodicalIF":10.5,"publicationDate":"2025-03-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143576303","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":"Supramolecular oral delivery technologies for polypeptide-based drugs","authors":"Jiawen Chen ,&nbsp;Tianqi Liu ,&nbsp;Mi Wang ,&nbsp;Beibei Lu ,&nbsp;De Bai ,&nbsp;Jiaqi Shang ,&nbsp;Yingjun Chen ,&nbsp;Jiaheng Zhang","doi":"10.1016/j.jconrel.2025.02.045","DOIUrl":"10.1016/j.jconrel.2025.02.045","url":null,"abstract":"<div><div>Oral supramolecular drug delivery systems (SDDSs) have shown promising potential, along with a rapid increase in the development of polypeptide-based drugs. Biofriendly, biocompatible, and multistimulation-responsive SDDSs achieve their unique deliverability via noncovalent bonds, which can encapsulate drugs and release them at the target site along the oral tract. In this review, we analyze the oral tract from an anatomical perspective and explain the potential physical, microenvironmental, and systematic barriers, as well as the properties of drug delivery. After understanding the specific environment at different oral sites, the application of SDDSs to the mouth, stomach, small intestine, and cell targeting is summarized. Finally, this review summarizes the application of SDDSs for the successful delivery of drugs and describes how to overcome the barriers of SDDSs in drug delivery using a more biofriendly approach.</div></div>","PeriodicalId":15450,"journal":{"name":"Journal of Controlled Release","volume":"381 ","pages":"Article 113549"},"PeriodicalIF":10.5,"publicationDate":"2025-03-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143576205","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":"Extracellular vesicle as a next-generation drug delivery platform for rheumatoid arthritis therapy","authors":"Yi Jin ,&nbsp;Cong Xu ,&nbsp;Yujuan Zhu ,&nbsp;Zhifeng Gu","doi":"10.1016/j.jconrel.2025.113610","DOIUrl":"10.1016/j.jconrel.2025.113610","url":null,"abstract":"<div><div>Rheumatoid arthritis (RA) is a systemic autoimmune disorder characterized by chronic inflammation and progressive damage to connective tissue. It is driven by dysregulated cellular homeostasis, often leading to autoimmune destruction and permanent disability in severe cases. Over the past decade, various drug delivery systems have been developed to enable targeted therapies for disease prevention, reduction, or suppression. As an emerging therapeutic platform, extracellular vesicles (EVs) offer several advantages over conventional drug delivery systems, including biocompatibility and low immunogenicity. Consequently, an increasing number of studies have explored EV-based delivery systems in the treatment of RA, leveraging their natural ability to evade phagocytosis, prolong in vivo half-life, and minimize the immunogenicity of therapeutic agents. In this review, we first provide an in-depth overview of the pathogenesis of RA and the current treatment landscape. We then discuss the classification and biological properties of EVs, their potential therapeutic mechanisms, and the latest advancements in EVs as drug delivery platforms for RA therapy. We emphasize the significance of EVs as carriers in RA treatment and their potential to revolutionize therapeutic strategies. Furthermore, we examine key technological innovations and the future trajectory of EV research, focusing on the challenges and opportunities in translating these platforms into clinical practice. Our discussion aims to offer a comprehensive understanding of the current state and future prospects of EV-based therapeutics in RA.</div></div>","PeriodicalId":15450,"journal":{"name":"Journal of Controlled Release","volume":"381 ","pages":"Article 113610"},"PeriodicalIF":10.5,"publicationDate":"2025-03-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143569422","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":"Mechanisms of receptor-mediated transcytosis at the blood-brain barrier","authors":"Habib Baghirov","doi":"10.1016/j.jconrel.2025.113595","DOIUrl":"10.1016/j.jconrel.2025.113595","url":null,"abstract":"<div><div>In receptor-mediated transcytosis (RMT) of large therapeutics across the blood-brain barrier (BBB), the construct - a macromolecule or a larger carrier with therapeutic payload - binds a protein on brain capillary endothelial cells (BCEC), with internalization and release into the brain parenchyma. The construct's internalization into, trafficking across and release from, but also possible entrapment within BCEC are affected by its engineered properties whose optimization has helped derive insights into transport mechanisms at BCEC. Furthermore, advances in multi-omics, as well as large-scale screening and directed evolution campaigns have helped identify new targets for RMT at BCEC.</div><div>In this perspective, I raise and reflect on some fundamental questions one can arrive at by comparing the engineered properties of BBB-targeted constructs and the properties of different target proteins. These questions concern the underlying, transcytosis-promoting factors that the optimization of constructs' engineered properties appears to converge on, the precise role of target proteins in RMT, the different mechanisms through which these targets may mediate construct trafficking, and the tentative criteria for target selection on BCEC. Based on these considerations I propose several scenarios and strategies to interfere with the construct's trafficking for more efficient internalization, transport through the endosomal network toward the abluminal membrane, and release from BCEC, both for smaller macromolecules and for larger carriers.</div></div>","PeriodicalId":15450,"journal":{"name":"Journal of Controlled Release","volume":"381 ","pages":"Article 113595"},"PeriodicalIF":10.5,"publicationDate":"2025-03-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143569414","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":"Cell-free DNA-scavenging nano/microsystems for immunotherapy","authors":"Wenhan Zhao ,&nbsp;Yang Zhou ,&nbsp;Lichen Yin","doi":"10.1016/j.jconrel.2025.113609","DOIUrl":"10.1016/j.jconrel.2025.113609","url":null,"abstract":"<div><div>In the context of inflammation, autoimmune diseases, infections, and cancers, cfDNA plays a pivotal role in disease progression through various mechanisms. Immunotherapies based on cfDNA scavenging has emerged as a promising approach for treating these conditions. This review offers a comprehensive exploration of cfDNA-binding and degradation strategies, providing detailed insights into the corresponding nano/microsystems for each approach. Nano/microsystems used for cfDNA binding include cationic polymers, nanoparticles, nanogels, and other materials that physically capture cfDNA <em>via</em> electrostatic interactions or other affinity mechanisms, thereby mitigating the immunological effects of cfDNA. Nano/microsystems designed for cfDNA degradation primarily involve DNase delivery systems and artificial enzymes with DNase-like activity, which degrade cfDNA through chemical cleavage. Furthermore, this review discusses the potential synergy between cfDNA-scavenging therapies and other treatment modalities, aiming to achieve more effective and comprehensive immunotherapy. By thoroughly analyzing these strategies, we aim to emphasize the transformative potential of cfDNA-scavenging nano/microsystems in advancing immunotherapy, and offer valuable perspectives for future research in this emerging field.</div></div>","PeriodicalId":15450,"journal":{"name":"Journal of Controlled Release","volume":"381 ","pages":"Article 113609"},"PeriodicalIF":10.5,"publicationDate":"2025-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143546635","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":"Multifunctional nanoparticle-mediated targeting of metabolic reprogramming and DNA damage response pathways to treat drug-resistant triple-negative breast cancer","authors":"Sifeng Zhu ,&nbsp;Chao Sun ,&nbsp;Zimin Cai ,&nbsp;Jibin Wu ,&nbsp;Xu Han ,&nbsp;Jue Wang ,&nbsp;Cheng Wang","doi":"10.1016/j.jconrel.2025.113601","DOIUrl":"10.1016/j.jconrel.2025.113601","url":null,"abstract":"<div><div>Multi-drug resistance and immunosuppressive triple-negative breast cancer (TNBC) is triggered by the Warburg effect, which promotes homologous recombination repair (HRR) and upregulates expression of P-glycoprotein (P-gp), in turn preventing DNA damage from chemotherapy and creating an immunosuppressive microenvironment. It is therefore of clinical relevance to develop an effective delivery system that targets metabolic reprogramming and DNA damage response pathways for the treatment of drug-resistant TNBC. Herein, a P-gp-inhibiting and GSH-responsive multifunctional drug carrier targeting integrin αvβ3 was synthesised for the delivery of Lonidamine-prodrug (M1, glycolysis inhibitor) and Senaparib (Se, Poly [ADP-ribose] polymerase inhibitor). The nanodrug delivery system (iPR@M1/Se nanoparticles) exhibit effective tumour penetration and P-gp inhibition, effectively inducing DNA damage and apoptosis in Olaparib-resistant TNBC cells <em>in vitro</em>, as well as a higher tumour inhibitory rate compared with that of Se (81.82 % ± 2.31 % <em>vs</em> 43.91 % ± 4.65 %) <em>in vivo</em>. Mechanistically, iPR@M1/Se nanoparticles not only reshaped the immunosuppressive microenvironment resulting from tumour glycolysis, but also downregulated the expression of HRR-related protein, fostering the cytoplasmic accumulation of DNA damage fragments, which induced activation of the cyclic GMP–AMP synthase (cGAS)/stimulator of interferon gene (STING) pathway. Experimental results show that iPR@M1/Se nanoparticles effectively promote dendritic cell maturation and T lymphocyte activation, which elicits long-term immune memory responses, and prevents tumour recurrence and lung metastasis. Therefore, these multifunctional nanoparticles have great potential and provide a clinically relevant and valuable option for Olaparib-resistant TNBC.</div></div>","PeriodicalId":15450,"journal":{"name":"Journal of Controlled Release","volume":"381 ","pages":"Article 113601"},"PeriodicalIF":10.5,"publicationDate":"2025-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143546216","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":"Innovative injectable, self-healing, exosome cross-linked biomimetic hydrogel for cartilage regeneration","authors":"Chenlin Tu ,&nbsp;Xiang Gao ,&nbsp;Hong Zheng ,&nbsp;Rui Huang ,&nbsp;Fengkai Yang ,&nbsp;Yeying Dong ,&nbsp;Kaipeng Jing ,&nbsp;Thomas Groth ,&nbsp;Mingyan Zhao","doi":"10.1016/j.jconrel.2025.113608","DOIUrl":"10.1016/j.jconrel.2025.113608","url":null,"abstract":"<div><div>The limited self-healing capacity of cartilage hinders its repair and regeneration at the defect sites. Recent research into small-molecular compounds has shown promise in achieving a better regeneration of cartilage. In this study, we encapsulate kartogenin (KGN) and transforming growth factor β1 (TGF-β1) within mesenchymal stem cells derived exosomes (EKT), and then coated them with succinylated chitosan (sCH) to create positively charged exosomes, termed CEKT. These CEKT exhibit exceptional chondrogenic promoting capabilities shown during <em>in vitro</em> studies with bone marrow derived mesenchymal stem cells (BMSCs). They also can penetrate deep into cartilage tissue derived from porcine knee joints guided by their positive charge. Subsequently, a dynamic exosomes-crosslinked hydrogel (Gel-CEKT) is fabricated by crosslinking CEKT with oxidized chondroitin sulfate (oCS) and Wharton's jelly (WJ) through imine bond formation. Physicochemical studies revealed the injectability, excellent adhesive, and self-healing abilities of this hydrogel, which enables minimally invasive and precise treatment of cartilage defects, assisted by the enriched and sustained administration of CEKT. <em>In vitro</em> cell experiments show that Gel-CEKT can efficiently recruit BMSCs and significantly promote the gene expression of Sox9 and protein expression of collagen II and aggrecan. Furthermore, we show in a rat model of cartilage defect that the Gel-CEKT demonstrates superior performance compared to Gel@EKT, which has freely encapsulated exosomes in the hydrogel. The freely encapsulated exosomes are rapidly released, whereas the exosome-crosslinked gel structure ensures sustained retention and functionality at the site of defect. This leads to impressive outcomings, including extensive new cartilage tissue formation, a smoother cartilage surface, significant chondrocyte production, and seamless integration with orderly and continuous structure formation between cartilage and subchondral bone. This study underscores the potential of exosomes-crosslinked hydrogels as a novel and promising therapeutic approach for clinical cartilage regeneration.</div></div>","PeriodicalId":15450,"journal":{"name":"Journal of Controlled Release","volume":"381 ","pages":"Article 113608"},"PeriodicalIF":10.5,"publicationDate":"2025-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143546218","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":"Multifunctional nanoparticles for immune regulation and oxidative stress alleviation in myocarditis","authors":"Zhou Ye ,&nbsp;Manman Zhu ,&nbsp;Shaojie Li ,&nbsp;Fan Zhang ,&nbsp;Yingqi Ran ,&nbsp;Cong Liu ,&nbsp;Xiangchang Xu ,&nbsp;Shujiao Liu ,&nbsp;Xiang Xie ,&nbsp;Yingchen Wang ,&nbsp;Lan Yao","doi":"10.1016/j.jconrel.2025.113607","DOIUrl":"10.1016/j.jconrel.2025.113607","url":null,"abstract":"<div><div>Cardiac autoimmune injury and oxidative stress play critical roles in the development of myocarditis. Promising approaches for treating this condition include suppressing excessive immune responses and reducing oxidative stress in the myocardium. The programmed cell death protein 1/programmed cell death ligand 1 (PD-1/PD-L1) axis is known to regulate immune responses and prevent damage caused by T-cell overactivation, while elevated reactive oxygen species (ROS) contribute to the progression of myocarditis. In this study, we developed multifunctional nanoparticles (PMN@EDR) that overexpress PD-L1 and are loaded with edaravone (EDR). The PMN@EDR NPs were successfully synthesized and comprehensively characterized. PMN@EDR effectively targeted inflammation-stimulated CD4⁺ T cells and damaged myocardial cells, inhibiting CD4⁺ T-cell proliferation, activation, and the release of pro-inflammatory cytokines via the PD-1/PD-L1 pathway. Additionally, PMN@EDR further suppressed CD4⁺ T-cell activation and alleviated HL-1 cardiomyocyte damage by releasing EDR to eliminate free radicals. For the in vivo treatment of myocarditis, compared to traditional single-target anti-inflammatory and antioxidant drugs, PMN@EDR not only reduced inflammation and the release of inflammatory mediators but also decreased ROS levels, thereby minimizing cardiomyocyte apoptosis and improving cardiac function. In conclusion, the PMN@EDR-based modulation of immune responses and oxidative stress offers a promising therapeutic strategy for myocarditis.</div></div>","PeriodicalId":15450,"journal":{"name":"Journal of Controlled Release","volume":"381 ","pages":"Article 113607"},"PeriodicalIF":10.5,"publicationDate":"2025-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143546628","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":"Stimuli-responsive polymer-dasatinib prodrug to reprogram cancer-associated fibroblasts for boosted immunotherapy","authors":"Yuxin Zhang ,&nbsp;Jie Zhou ,&nbsp;Yiyan Wang ,&nbsp;Yaping Wu ,&nbsp;Yunkun Li ,&nbsp;Bing Wang ,&nbsp;Guohao Liu ,&nbsp;Qiyong Gong ,&nbsp;Kui Luo ,&nbsp;Jing Jing","doi":"10.1016/j.jconrel.2025.113606","DOIUrl":"10.1016/j.jconrel.2025.113606","url":null,"abstract":"<div><div>The barriers from cancer-associated fibroblasts (CAFs) have diminished the clinical efficacy of immunotherapy for triple-negative breast cancer (TNBC). The obstacles from CAFs often result in poor drug penetration, constrained cytotoxic T lymphocyte infiltration, and an immunosuppressive microenvironment. Herein, chondroitin sulfate (CS) was engineered to conjugate dasatinib (DAS), a tyrosine kinase inhibitor, via the cathepsin B (CTSB)-responsive GFLG linker to produce CS-GFLG-DAS (CGD), which could be employed to reverse the CAF phenotype and regulate the biosynthesis of extracellular matrix (ECM), thus enhancing the efficacy of immune checkpoint blockade (ICB) therapy. Upon reaching the tumor site, DAS released from CGD in response to overexpressed CTSB in the tumor microenvironment could transform CAFs into a quiescent state instead of killing them to prevent CAFs from producing abundant ECM, thereby promoting deep penetration of CGD to effectively kill tumor cells. In addition, ECM remodeling facilitated tumor infiltration of cytotoxic T lymphocytes, synergistically enhancing the anti-PD-1 efficacy in the 4T1 tumor-bearing mice. In summary, this prodrug enhanced deep drug penetration and therapeutic sensitivity of anti-PD-1 by regulating CAFs, providing new insights into optimizing immunotherapy in treating fibrotic tumors via nanomedicine.</div></div>","PeriodicalId":15450,"journal":{"name":"Journal of Controlled Release","volume":"381 ","pages":"Article 113606"},"PeriodicalIF":10.5,"publicationDate":"2025-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143546536","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}