Pub Date : 2025-03-05DOI: 10.1016/j.jconrel.2025.113609
Wenhan Zhao, Yang Zhou, Lichen Yin
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 via 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.
{"title":"Cell-free DNA-scavenging nano/microsystems for immunotherapy","authors":"Wenhan Zhao, Yang Zhou, Lichen Yin","doi":"10.1016/j.jconrel.2025.113609","DOIUrl":"https://doi.org/10.1016/j.jconrel.2025.113609","url":null,"abstract":"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.","PeriodicalId":15450,"journal":{"name":"Journal of Controlled Release","volume":"36 1","pages":""},"PeriodicalIF":10.8,"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}
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 in vitro, as well as a higher tumour inhibitory rate compared with that of Se (81.82 % ± 2.31 % vs 43.91 % ± 4.65 %) in vivo. 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.
{"title":"Multifunctional nanoparticle-mediated targeting of metabolic reprogramming and DNA damage response pathways to treat drug-resistant triple-negative breast cancer","authors":"Sifeng Zhu, Chao Sun, Zimin Cai, Jibin Wu, Xu Han, Jue Wang, Cheng Wang","doi":"10.1016/j.jconrel.2025.113601","DOIUrl":"https://doi.org/10.1016/j.jconrel.2025.113601","url":null,"abstract":"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.","PeriodicalId":15450,"journal":{"name":"Journal of Controlled Release","volume":"141 1","pages":""},"PeriodicalIF":10.8,"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}
Pub Date : 2025-03-05DOI: 10.1016/j.jconrel.2025.113608
Chenlin Tu, Xiang Gao, Hong Zheng, Rui Huang, Fengkai Yang, Yeying Dong, Kaipeng Jing, Thomas Groth, Mingyan Zhao
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 in vitro 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. In vitro 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.
{"title":"Innovative injectable, self-healing, exosome cross-linked biomimetic hydrogel for cartilage regeneration","authors":"Chenlin Tu, Xiang Gao, Hong Zheng, Rui Huang, Fengkai Yang, Yeying Dong, Kaipeng Jing, Thomas Groth, Mingyan Zhao","doi":"10.1016/j.jconrel.2025.113608","DOIUrl":"https://doi.org/10.1016/j.jconrel.2025.113608","url":null,"abstract":"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.","PeriodicalId":15450,"journal":{"name":"Journal of Controlled Release","volume":"2 1","pages":""},"PeriodicalIF":10.8,"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}
Pub Date : 2025-03-05DOI: 10.1016/j.jconrel.2025.113602
Marco Block, Achim Grube, Achim Göpferich, Christoph Saal, Blessing C. Ilochonwu, Álvaro Cárcamo-Martínez, Grazia Giorgio, Remko A. Bakker, Richard Deanne, Joachim Schäfer, Brennan Walder, Roman Simon
Current standard pharmacological treatment of retinal vascular diseases requires frequent intravitreal injection every 4–12 weeks. Active pharmaceutical ingredients (APIs) with better pharmacokinetics (PK), allowing less frequent administrations, remain to be discovered and developed. In preclinical stage mostly small molecule New Chemical Entities (NCEs) and peptides represent promising candidates. However, they typically suffer from fast clearance from the eye upon intravitreal injection, which confines support of animal models as sufficient exposure over 1–4 weeks in the eye is not reached. Addressing this need of extended-release (XR) formulations to enable such animal models, we hereby present chitosan embedded silica particles in suspension (CHESS). We identified non-mesoporous silica matrix particles as suitable biodegradable XR formulation and established a preparation method to control their degree of condensation, erosion rate and finally the release rate. Applicability for different API candidates was demonstrated by successful embedding of two model small molecules and one model peptide at high drug loads of >20 %, respectively. The ability to control release rate was demonstrated in vitro. High intravitreal mobility, which is a disadvantage of uncoated silica microparticles and other intravitreally applied XR microparticle formulations, was reduced by surface-coating with a polycationic chitosan-derivative. This leads to formation of stable depots in the vitreous after injection, which can be easily separated from the retina, facilitating PK analysis and pharmacodynamic (PD) readouts. Furthermore, we showed good tolerability and low toxicity on ARPE-19 cells.
{"title":"Surface-coated silica microparticles: In vitro and ex vivo evaluation of a preclinical extended release platform conceived for intravitreal injection","authors":"Marco Block, Achim Grube, Achim Göpferich, Christoph Saal, Blessing C. Ilochonwu, Álvaro Cárcamo-Martínez, Grazia Giorgio, Remko A. Bakker, Richard Deanne, Joachim Schäfer, Brennan Walder, Roman Simon","doi":"10.1016/j.jconrel.2025.113602","DOIUrl":"https://doi.org/10.1016/j.jconrel.2025.113602","url":null,"abstract":"Current standard pharmacological treatment of retinal vascular diseases requires frequent intravitreal injection every 4–12 weeks. Active pharmaceutical ingredients (APIs) with better pharmacokinetics (PK), allowing less frequent administrations, remain to be discovered and developed. In preclinical stage mostly small molecule New Chemical Entities (NCEs) and peptides represent promising candidates. However, they typically suffer from fast clearance from the eye upon intravitreal injection, which confines support of animal models as sufficient exposure over 1–4 weeks in the eye is not reached. Addressing this need of extended-release (XR) formulations to enable such animal models, we hereby present chitosan embedded silica particles in suspension (CHESS). We identified non-mesoporous silica matrix particles as suitable biodegradable XR formulation and established a preparation method to control their degree of condensation, erosion rate and finally the release rate. Applicability for different API candidates was demonstrated by successful embedding of two model small molecules and one model peptide at high drug loads of >20 %, respectively. The ability to control release rate was demonstrated <em>in vitro</em>. High intravitreal mobility, which is a disadvantage of uncoated silica microparticles and other intravitreally applied XR microparticle formulations, was reduced by surface-coating with a polycationic chitosan-derivative. This leads to formation of stable depots in the vitreous after injection, which can be easily separated from the retina, facilitating PK analysis and pharmacodynamic (PD) readouts. Furthermore, we showed good tolerability and low toxicity on ARPE-19 cells.","PeriodicalId":15450,"journal":{"name":"Journal of Controlled Release","volume":"211 1","pages":""},"PeriodicalIF":10.8,"publicationDate":"2025-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143546535","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}
Pub Date : 2025-03-05DOI: 10.1016/j.jconrel.2025.113606
Yuxin Zhang, Jie Zhou, Yiyan Wang, Yaping Wu, Yunkun Li, Bing Wang, Guohao Liu, Qiyong Gong, Kui Luo, Jing Jing
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 4 T1 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.
{"title":"Stimuli-responsive polymer-dasatinib prodrug to reprogram cancer-associated fibroblasts for boosted immunotherapy","authors":"Yuxin Zhang, Jie Zhou, Yiyan Wang, Yaping Wu, Yunkun Li, Bing Wang, Guohao Liu, Qiyong Gong, Kui Luo, Jing Jing","doi":"10.1016/j.jconrel.2025.113606","DOIUrl":"https://doi.org/10.1016/j.jconrel.2025.113606","url":null,"abstract":"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 4 T1 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.","PeriodicalId":15450,"journal":{"name":"Journal of Controlled Release","volume":"2 1","pages":""},"PeriodicalIF":10.8,"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}
Pub Date : 2025-03-05DOI: 10.1016/j.jconrel.2025.113607
Zhou Ye, Manman Zhu, Shaojie Li, Fan Zhang, Yingqi Ran, Cong Liu, Xiangchang Xu, Shujiao Liu, Xiang Xie, Yingchen Wang, Lan Yao
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.
{"title":"Multifunctional nanoparticles for immune regulation and oxidative stress alleviation in myocarditis","authors":"Zhou Ye, Manman Zhu, Shaojie Li, Fan Zhang, Yingqi Ran, Cong Liu, Xiangchang Xu, Shujiao Liu, Xiang Xie, Yingchen Wang, Lan Yao","doi":"10.1016/j.jconrel.2025.113607","DOIUrl":"https://doi.org/10.1016/j.jconrel.2025.113607","url":null,"abstract":"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<sup>+</sup> T cells and damaged myocardial cells, inhibiting CD4<sup>+</sup> T-cell proliferation, activation, and the release of pro-inflammatory cytokines via the PD-1/PD-L1 pathway. Additionally, PMN@EDR further suppressed CD4<sup>+</sup> 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.","PeriodicalId":15450,"journal":{"name":"Journal of Controlled Release","volume":"30 1","pages":""},"PeriodicalIF":10.8,"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}
Pub Date : 2025-03-04DOI: 10.1016/j.jconrel.2025.113599
Pieter Vader
No Abstract
无摘要
{"title":"Extracellular vesicles for drug delivery: A major interest for the Journal of Controlled Release","authors":"Pieter Vader","doi":"10.1016/j.jconrel.2025.113599","DOIUrl":"https://doi.org/10.1016/j.jconrel.2025.113599","url":null,"abstract":"No Abstract","PeriodicalId":15450,"journal":{"name":"Journal of Controlled Release","volume":"28 1","pages":""},"PeriodicalIF":10.8,"publicationDate":"2025-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143546217","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}
The importance of the tumor microenvironment in dynamically modulating neoplastic process, fostering proliferation, survival and migration is now widely appreciated. Therapeutics directed to various components of tumor microenvironment, especially tumor-associated macrophages and myeloid-derived suppressor cells (MDSCs), have become an attractive avenue for cancer immunotherapy. Virus-like particles (VLPs) derived from cowpea chlorotic mottle viruses (CCMV) have been used extensively in biotechnology and are ideal platforms for the targeted delivery of therapeutic drugs for cancer immunotherapy. Here, oxidative dsDNAs, which have excellent immunostimulatory effects, are encapsulated into CCMV (CPD VLPs). CPD VLPs could be effectively taken up by macrophages and subsequently trigger Cyclic GMP-AMP synthase-stimulator of interferon genes pathway and NLRP3/Caspase-1/Gasdermin D -dependent pyroptosis pathway. To increase tumor-targeting specificity and reduce toxicity in bystander healthy tissues, peptides targeting MDSCs are conjugated to the exterior surfaces of the CPD VLPs named CPD-TP VLPs. CPD-TP VLPs can home to tumor side and induce a robust antitumor response by reprogramming tumor microenvironment. Notably, CPD-TP VLPs administration is also efficacious against lung metastasis from breast cancer. Moreover, the combination of CPD-TP VLPs with programmed cell death protein 1 (PD-1) blockade could improve therapeutic response of PD-1 antibody treatment in “immune-cold” mouse tumor models. Therefore, this study presents a novel design for VLP-based cancer vaccine.
{"title":"Myeloid-derived suppressor cell-targeted virus-like particles synergistically activate innate immune response for cancer immunotherapy","authors":"Zhixiong Zhu, Shuqin Cao, Hanwen Li, Zongliang Zhang, Qizhong Lu, Hexian Li, Luxuan Shen, Zeng Wang, Nian Yang, Jiayun Yu, Jianshu Li, Meijun Zheng, Chunlai Nie, Aiping Tong, Bin Shao","doi":"10.1016/j.jconrel.2025.113603","DOIUrl":"https://doi.org/10.1016/j.jconrel.2025.113603","url":null,"abstract":"The importance of the tumor microenvironment in dynamically modulating neoplastic process, fostering proliferation, survival and migration is now widely appreciated. Therapeutics directed to various components of tumor microenvironment, especially tumor-associated macrophages and myeloid-derived suppressor cells (MDSCs), have become an attractive avenue for cancer immunotherapy. Virus-like particles (VLPs) derived from cowpea chlorotic mottle viruses (CCMV) have been used extensively in biotechnology and are ideal platforms for the targeted delivery of therapeutic drugs for cancer immunotherapy. Here, oxidative dsDNAs, which have excellent immunostimulatory effects, are encapsulated into CCMV (CPD VLPs). CPD VLPs could be effectively taken up by macrophages and subsequently trigger Cyclic GMP-AMP synthase-stimulator of interferon genes pathway and NLRP3/Caspase-1/Gasdermin D -dependent pyroptosis pathway. To increase tumor-targeting specificity and reduce toxicity in bystander healthy tissues, peptides targeting MDSCs are conjugated to the exterior surfaces of the CPD VLPs named CPD-TP VLPs. CPD-TP VLPs can home to tumor side and induce a robust antitumor response by reprogramming tumor microenvironment. Notably, CPD-TP VLPs administration is also efficacious against lung metastasis from breast cancer. Moreover, the combination of CPD-TP VLPs with programmed cell death protein 1 (PD-1) blockade could improve therapeutic response of PD-1 antibody treatment in “immune-cold” mouse tumor models. Therefore, this study presents a novel design for VLP-based cancer vaccine.","PeriodicalId":15450,"journal":{"name":"Journal of Controlled Release","volume":"34 1","pages":""},"PeriodicalIF":10.8,"publicationDate":"2025-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143538650","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}
Glaucoma is a serious cause of permanent blindness worldwide, mainly caused by inflammation and degeneration of the optic nerve. However, current treatments using systemically administered drugs have limited effectiveness due to various biological barriers that prevent their biodistribution in the eye. To overcome these challenges, we developed a new therapy that utilizes intranasal delivery to retinal lesions. In this therapy, we used platelet extracellular vesicles (pEVs) as carriers for epigallocatechin gallate (EGCG), which is known for its neuroprotective, anti-inflammatory, and immunomodulatory properties. We hypothesized that this therapy could overcome ocular barriers, increase drug bioavailability, and mitigate glaucoma progression. We conducted extensive characterization of the biochemical and biophysical properties of the EGCG-pEVs, and the results were promising. In vivo tests using an animal model of dexamethasone-induced glaucoma showed that intranasal administration of EGCG-pEVs was safe and had superior drug delivery and therapeutic efficacy, including anti-inflammatory, immunomodulatory, and intraocular pressure-reducing effects, compared to an intraperitoneal injection or ophthalmic drug administration routes. This unique mode of drug administration shows great potential for clinical applications in ophthalmology.
{"title":"Intranasal delivery of epigallocatechin gallate-laden platelet extracellular vesicles for mitigating retinal glaucoma","authors":"Wen-Yu Pan, Pei-Wei Weng, Shen-Han Wu, Chi-Hung Hsiao, Pei-Ru Jheng, Huynh-Ngoc-Truc Nguyen, Ching-Li Tseng, Thierry Burnou, Lekshmi Rethi, Hieu Trung Nguyen, Wei-Yung Huang, Tsung-Jen Wang, Andrew E.-Y. Chuang","doi":"10.1016/j.jconrel.2025.113596","DOIUrl":"https://doi.org/10.1016/j.jconrel.2025.113596","url":null,"abstract":"Glaucoma is a serious cause of permanent blindness worldwide, mainly caused by inflammation and degeneration of the optic nerve. However, current treatments using systemically administered drugs have limited effectiveness due to various biological barriers that prevent their biodistribution in the eye. To overcome these challenges, we developed a new therapy that utilizes intranasal delivery to retinal lesions. In this therapy, we used platelet extracellular vesicles (pEVs) as carriers for epigallocatechin gallate (EGCG), which is known for its neuroprotective, anti-inflammatory, and immunomodulatory properties. We hypothesized that this therapy could overcome ocular barriers, increase drug bioavailability, and mitigate glaucoma progression. We conducted extensive characterization of the biochemical and biophysical properties of the EGCG-pEVs, and the results were promising. In vivo tests using an animal model of dexamethasone-induced glaucoma showed that intranasal administration of EGCG-pEVs was safe and had superior drug delivery and therapeutic efficacy, including anti-inflammatory, immunomodulatory, and intraocular pressure-reducing effects, compared to an intraperitoneal injection or ophthalmic drug administration routes. This unique mode of drug administration shows great potential for clinical applications in ophthalmology.","PeriodicalId":15450,"journal":{"name":"Journal of Controlled Release","volume":"1 1","pages":""},"PeriodicalIF":10.8,"publicationDate":"2025-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143532803","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}
Atherosclerosis (AS) therapy has been commonly based on lipid-lowering agents (e.g., statins), supplemented by other therapies, such as anti-inflammatory agents and antioxidants, through traditional Chinese herbs. Ferroptosis, a form of regulated cell death characterized by iron-dependent lipid peroxidation, has been implicated in the progression of AS, particularly in macrophages. In the study, we constructed a macrophage targeted hybridization nanodrug of HMLRPP NPs, which used Pit-loaded Poly(lactic-co-glycolic) acid (PLGA) nanoparticles and Res-loaded liposomes (Lipo) as nano-core, then, coated with a macrophage membrane hybridized by hyaluronic acid (HA). The nanodrug prolonged blood circulation time and achieved optimal Res and Pit accumulation in the atherosclerotic plaques by effectively evading immune system clearance. In vivo studies demonstrated that HMLRPP NPs significantly attenuated plaque progression, characterized by decreased plaque area, less lipid deposition, and increased collagen. Meanwhile, HMLRPP NPs inhibited macrophage ferroptosis by decreasing the expression of β-Hydroxybutyrate dehydrogenase 1 (BDH1), Orosomucoid 1 (ORM1) and enhancing the expression of Ribosomal protein S27-like (RPS27L), which resulted in the alleviation of lipid accumulation and inflammation. Our data suggest that the HMLRPP nanodrug delivery system with ferroptosis-regulating capability provides a feasible therapeutic strategy for atherosclerosis.
{"title":"Pitavastatin and resveratrol bio-nanocomplexes against hyperhomocysteinemia-induced atherosclerosis via blocking ferroptosis-related lipid deposition","authors":"Anning Yang, Hongwen Zhang, Huiping Zhang, Nan Li, Cong Chen, Xiaoling Yang, Jue Tian, Jianmin Sun, Guizhong Li, Yue Sun, Bin Liu, Yideng Jiang","doi":"10.1016/j.jconrel.2025.113598","DOIUrl":"https://doi.org/10.1016/j.jconrel.2025.113598","url":null,"abstract":"Atherosclerosis (AS) therapy has been commonly based on lipid-lowering agents (<em>e.g.</em>, statins), supplemented by other therapies, such as anti-inflammatory agents and antioxidants, through traditional Chinese herbs. Ferroptosis, a form of regulated cell death characterized by iron-dependent lipid peroxidation, has been implicated in the progression of AS, particularly in macrophages. In the study, we constructed a macrophage targeted hybridization nanodrug of HMLRPP NPs, which used Pit-loaded Poly(lactic-<em>co</em>-glycolic) acid (PLGA) nanoparticles and Res-loaded liposomes (Lipo) as nano-core, then, coated with a macrophage membrane hybridized by hyaluronic acid (HA). The nanodrug prolonged blood circulation time and achieved optimal Res and Pit accumulation in the atherosclerotic plaques by effectively evading immune system clearance. <em>In vivo</em> studies demonstrated that HMLRPP NPs significantly attenuated plaque progression, characterized by decreased plaque area, less lipid deposition, and increased collagen. Meanwhile, HMLRPP NPs inhibited macrophage ferroptosis by decreasing the expression of β-Hydroxybutyrate dehydrogenase 1 (BDH1), Orosomucoid 1 (ORM1) and enhancing the expression of Ribosomal protein S27-like (RPS27L), which resulted in the alleviation of lipid accumulation and inflammation. Our data suggest that the HMLRPP nanodrug delivery system with ferroptosis-regulating capability provides a feasible therapeutic strategy for atherosclerosis.","PeriodicalId":15450,"journal":{"name":"Journal of Controlled Release","volume":"32 1","pages":""},"PeriodicalIF":10.8,"publicationDate":"2025-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143532797","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}
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