Pub Date : 2025-12-19DOI: 10.1016/j.jconrel.2025.114561
Neona M. Lowe , Bryan B. Nguyen , Rachel R. Mizenko , Anastasia Trushchankova , Dustin J. Hadley , Alyssa Panitch , Randy P. Carney
Extracellular vesicles (EVs) are heterogenous lipid-bilayer wrapped nanoparticles with high potential as next generation drug delivery vehicles. Here we explore the use of EVs as a novel carrier of therapeutic cell penetrating peptides (CPPs). The loading of five different CPPs was characterized using single particle flow cytometry. We demonstrate that the different physiochemical properties of various CPP classes affect their interaction and loading into EVs. We reveal that CPPs partially, and passively, penetrate to the EV lumen, that loading is independent of EV source, and that EV surface proteins play a role in loading efficiency for cationic CPPs (i.e., TAT). Finally, the CPP therapeutic MK2i, which has been previously demonstrated to aid in the suppression of pulmonary fibrosis, was loaded into healthy fibroblast or diseased myofibroblast EVs. MK2i-loaded fibroblast EVs exhibited greater efficacy in both a preventative and treatment in vitro model of pulmonary fibrosis compared to MK2i-loaded myofibroblast EVs and free MK2i peptide. Together, this demonstrates the potential of CPP-loaded EVs as a targeted drug delivery system for the treatment of pulmonary fibrosis.
{"title":"Loading of therapeutic cell penetrating peptides into extracellular vesicles for pulmonary fibrosis","authors":"Neona M. Lowe , Bryan B. Nguyen , Rachel R. Mizenko , Anastasia Trushchankova , Dustin J. Hadley , Alyssa Panitch , Randy P. Carney","doi":"10.1016/j.jconrel.2025.114561","DOIUrl":"10.1016/j.jconrel.2025.114561","url":null,"abstract":"<div><div>Extracellular vesicles (EVs) are heterogenous lipid-bilayer wrapped nanoparticles with high potential as next generation drug delivery vehicles. Here we explore the use of EVs as a novel carrier of therapeutic cell penetrating peptides (CPPs). The loading of five different CPPs was characterized using single particle flow cytometry. We demonstrate that the different physiochemical properties of various CPP classes affect their interaction and loading into EVs. We reveal that CPPs partially, and passively, penetrate to the EV lumen, that loading is independent of EV source, and that EV surface proteins play a role in loading efficiency for cationic CPPs (i.e., TAT). Finally, the CPP therapeutic MK2i, which has been previously demonstrated to aid in the suppression of pulmonary fibrosis, was loaded into healthy fibroblast or diseased myofibroblast EVs. MK2i-loaded fibroblast EVs exhibited greater efficacy in both a preventative and treatment in vitro model of pulmonary fibrosis compared to MK2i-loaded myofibroblast EVs and free MK2i peptide. Together, this demonstrates the potential of CPP-loaded EVs as a targeted drug delivery system for the treatment of pulmonary fibrosis.</div></div>","PeriodicalId":15450,"journal":{"name":"Journal of Controlled Release","volume":"390 ","pages":"Article 114561"},"PeriodicalIF":11.5,"publicationDate":"2025-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145784472","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 : 2025-12-18DOI: 10.1016/j.jconrel.2025.114558
Marieke Theodora Roefs , Johanna Gamauf , Barbara Kroenigsberger , Alessia Brancolini , Michael W. Traxlmayr , Elsa Arcalis , Jaroslaw Jacak , Marcelle van Mechelen , Jean-Paul Prieels , Regina Grillari-Voglauer , Johannes Grillari , Madhusudhan Reddy Bobbili
Extracellular vesicles (EVs) are cell-derived nanovesicles with promising potential for drug delivery due to their low toxicity and immunogenicity. However, their clinical application is limited by poor targeting to sites of interest. Existing strategies to engineer targeted EVs often require genetic donor cell modification for each specific target, making the process time-consuming and costly. To overcome this, we developed a versatile targeting platform using the fluorescein-specific single-chain variable fragment (scFv) 4 M5.3, integrated into a CD81-based Snorkel-tag construct for surface display on EVs. A C-terminal HA-tag, separated by a PreScission protease (PS) site, allows selective purification of targeted EVs and removal of unbound targeting moieties. This design enables functionalization of EVs with any fluorescein-conjugated targeting molecule. We tested various construct modifications (cMyc, FLAG, PS-HA), which showed differing expression levels and FITC-antibody binding by HEK293 cells and their EVs. As proof of concept, we generated EVs targeting human HER2 and mouse CCR2 by capturing FITC-labeled antibodies, which bound specifically to HER2+ NCI-N87 and CCR2+ RAW264.7 cells. The technology was also successfully applied to transmembrane protein CD9 and WJ-MSC/TERT273-derived EVs. In summary, we present a robust, adaptable method for generating EVs with customizable targeting, enabling high-throughput target screening and accelerating the development of EV-based therapeutics.
{"title":"Rapid extracellular vesicle surface decoration with targeting moieties based on a fluorescein binding single chain variable fragment snorkel","authors":"Marieke Theodora Roefs , Johanna Gamauf , Barbara Kroenigsberger , Alessia Brancolini , Michael W. Traxlmayr , Elsa Arcalis , Jaroslaw Jacak , Marcelle van Mechelen , Jean-Paul Prieels , Regina Grillari-Voglauer , Johannes Grillari , Madhusudhan Reddy Bobbili","doi":"10.1016/j.jconrel.2025.114558","DOIUrl":"10.1016/j.jconrel.2025.114558","url":null,"abstract":"<div><div>Extracellular vesicles (EVs) are cell-derived nanovesicles with promising potential for drug delivery due to their low toxicity and immunogenicity. However, their clinical application is limited by poor targeting to sites of interest. Existing strategies to engineer targeted EVs often require genetic donor cell modification for each specific target, making the process time-consuming and costly. To overcome this, we developed a versatile targeting platform using the fluorescein-specific single-chain variable fragment (scFv) 4 M5.3, integrated into a CD81-based Snorkel-tag construct for surface display on EVs. A C-terminal HA-tag, separated by a PreScission protease (PS) site, allows selective purification of targeted EVs and removal of unbound targeting moieties. This design enables functionalization of EVs with any fluorescein-conjugated targeting molecule. We tested various construct modifications (cMyc, FLAG, PS-HA), which showed differing expression levels and FITC-antibody binding by HEK293 cells and their EVs. As proof of concept, we generated EVs targeting human HER2 and mouse CCR2 by capturing FITC-labeled antibodies, which bound specifically to HER2+ NCI-N87 and CCR2+ RAW264.7 cells. The technology was also successfully applied to transmembrane protein CD9 and WJ-MSC/TERT273-derived EVs. In summary, we present a robust, adaptable method for generating EVs with customizable targeting, enabling high-throughput target screening and accelerating the development of EV-based therapeutics.</div></div>","PeriodicalId":15450,"journal":{"name":"Journal of Controlled Release","volume":"390 ","pages":"Article 114558"},"PeriodicalIF":11.5,"publicationDate":"2025-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145784478","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 : 2025-12-18DOI: 10.1016/j.jconrel.2025.114557
Cléa Belin , Emma Lenglet , Marie-Lynn Al-Hawat , Justine Caron , Emma Grande Bartumeu , Sarah Djebbar , Simon Matoori
Vesicular microreactors have gained broad interest in drug delivery, biodetoxification, and green chemistry. We have expanded their use to diagnostic applications by leveraging the selective permeability of the vesicular membrane. In the past, we developed a transmembrane pH-gradient polymeric microreactor to sense ammonia, a widely used biomarker in liver disease. After diffusing across the membrane, ammonia is protonated in the acidic lumen of the polymersome. The pH increase is detected by a pH-sensitive near-infrared fluorophore in the lumen. The high ammonia selectivity of this polymersome microreactor relies on the highly hydrophobic membrane of poly(styrene)-b-poly(ethylene glycol) polymersomes. In this study, we are combining ammonia-sensing polymersomes with a highly selective ammonia-generating enzyme, urease, to expand the analyte space and enable urea sensing in whole blood. Blood urea is a widely used biomarker in kidney disease, notably to determine the adequate duration of hemodialysis. In clinical routine, blood urea measurements are performed in centralized laboratories. A bedside test would enable real-time urea monitoring during hemodialysis with the potential to reduce the risk of over- and underdialysis. We first optimized the assay components and parameters (PS-b-PEG polymersomes, pH-sensitive dye, urease, incubation time and temperature) to optimize the sensor response and kinetics in phosphate buffer at pH 7.4. The urease-coupled polymersome assay was subsequently tested in urea-spiked fresh mouse blood. We observed a rapid and linear response at clinically relevant urea concentrations. Based on these results, the assay was tested in an IRB-approved study in healthy volunteers. In fresh capillary blood, the assay was able to discriminate three clinically relevant spiked urea concentrations in under one minute. Therefore, coupling the urease-catalyzed hydrolysis of urea with ammonia-sensing polymersomes yielded a blood urea assay with high selectivity and a rapid response at clinically relevant concentrations. These results highlight the potential of combining a highly selective ammonia-generating enzyme with ammonia-sensing polymersome microreactors for blood metabolite sensing at the point-of-care.
{"title":"Enzyme-coupled polymersome microreactor for point-of-care blood urea sensing","authors":"Cléa Belin , Emma Lenglet , Marie-Lynn Al-Hawat , Justine Caron , Emma Grande Bartumeu , Sarah Djebbar , Simon Matoori","doi":"10.1016/j.jconrel.2025.114557","DOIUrl":"10.1016/j.jconrel.2025.114557","url":null,"abstract":"<div><div>Vesicular microreactors have gained broad interest in drug delivery, biodetoxification, and green chemistry. We have expanded their use to diagnostic applications by leveraging the selective permeability of the vesicular membrane. In the past, we developed a transmembrane pH-gradient polymeric microreactor to sense ammonia, a widely used biomarker in liver disease. After diffusing across the membrane, ammonia is protonated in the acidic lumen of the polymersome. The pH increase is detected by a pH-sensitive near-infrared fluorophore in the lumen. The high ammonia selectivity of this polymersome microreactor relies on the highly hydrophobic membrane of poly(styrene)-<em>b</em>-poly(ethylene glycol) polymersomes. In this study, we are combining ammonia-sensing polymersomes with a highly selective ammonia-generating enzyme, urease, to expand the analyte space and enable urea sensing in whole blood. Blood urea is a widely used biomarker in kidney disease, notably to determine the adequate duration of hemodialysis. In clinical routine, blood urea measurements are performed in centralized laboratories. A bedside test would enable real-time urea monitoring during hemodialysis with the potential to reduce the risk of over- and underdialysis. We first optimized the assay components and parameters (PS-<em>b</em>-PEG polymersomes, pH-sensitive dye, urease, incubation time and temperature) to optimize the sensor response and kinetics in phosphate buffer at pH 7.4. The urease-coupled polymersome assay was subsequently tested in urea-spiked fresh mouse blood. We observed a rapid and linear response at clinically relevant urea concentrations. Based on these results, the assay was tested in an IRB-approved study in healthy volunteers. In fresh capillary blood, the assay was able to discriminate three clinically relevant spiked urea concentrations in under one minute. Therefore, coupling the urease-catalyzed hydrolysis of urea with ammonia-sensing polymersomes yielded a blood urea assay with high selectivity and a rapid response at clinically relevant concentrations. These results highlight the potential of combining a highly selective ammonia-generating enzyme with ammonia-sensing polymersome microreactors for blood metabolite sensing at the point-of-care.</div></div>","PeriodicalId":15450,"journal":{"name":"Journal of Controlled Release","volume":"390 ","pages":"Article 114557"},"PeriodicalIF":11.5,"publicationDate":"2025-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145784479","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 : 2025-12-17DOI: 10.1016/j.jconrel.2025.114547
Jun Shen , Yongjie Zhu , Tingting Li , Xia Wu , Jin Hai Zheng , Junfeng Shi
The clinical translation of bacteria-mediated immunotherapy has been hindered by severe systemic toxicity due to off-target bacterial colonization. To address these limitations, we developed a glutathione (GSH)-responsive self-assembling peptide that forms a nanofibrous coating on Salmonella typhimurium, enabling spatiotemporal control over bacterial activity. The peptide binds lipopolysaccharides on the bacterial surface via electrostatic and hydrogen bonding interactions, forming a stable protective layer that shields immunogenic epitopes. In the reductive tumor microenvironment, elevated GSH levels trigger disulfide bond cleavage, resulting in disassembly of the peptide shell and controlled bacterial release at tumor sites. In vivo, 10 μM and 20 μM peptide coatings enhanced tumor accumulation by ∼2.5- and ∼ 1.5-fold, respectively, primarily by enhancing tumor retention and reducing pre-targeting immune clearance. This was accompanied by an increase in tumor-infiltrating neutrophils, key effectors in tumor regression. Importantly, this occurred with markedly reduced systemic inflammation and organ toxicity compared with unmodified bacteria. This strategy offers a promising platform for improving the precision and safety of bacterial immunotherapy, advancing its potential for clinical application in cancer treatment.
{"title":"Glutathione-responsive self-assembling peptide-coated Salmonella for antitumor therapy","authors":"Jun Shen , Yongjie Zhu , Tingting Li , Xia Wu , Jin Hai Zheng , Junfeng Shi","doi":"10.1016/j.jconrel.2025.114547","DOIUrl":"10.1016/j.jconrel.2025.114547","url":null,"abstract":"<div><div>The clinical translation of bacteria-mediated immunotherapy has been hindered by severe systemic toxicity due to off-target bacterial colonization. To address these limitations, we developed a glutathione (GSH)-responsive self-assembling peptide that forms a nanofibrous coating on <em>Salmonella typhimurium</em>, enabling spatiotemporal control over bacterial activity. The peptide binds lipopolysaccharides on the bacterial surface via electrostatic and hydrogen bonding interactions, forming a stable protective layer that shields immunogenic epitopes. In the reductive tumor microenvironment, elevated GSH levels trigger disulfide bond cleavage, resulting in disassembly of the peptide shell and controlled bacterial release at tumor sites. In vivo, 10 μM and 20 μM peptide coatings enhanced tumor accumulation by ∼2.5- and ∼ 1.5-fold, respectively, primarily by enhancing tumor retention and reducing pre-targeting immune clearance. This was accompanied by an increase in tumor-infiltrating neutrophils, key effectors in tumor regression. Importantly, this occurred with markedly reduced systemic inflammation and organ toxicity compared with unmodified bacteria. This strategy offers a promising platform for improving the precision and safety of bacterial immunotherapy, advancing its potential for clinical application in cancer treatment.</div></div>","PeriodicalId":15450,"journal":{"name":"Journal of Controlled Release","volume":"390 ","pages":"Article 114547"},"PeriodicalIF":11.5,"publicationDate":"2025-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145771267","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 : 2025-12-17DOI: 10.1016/j.jconrel.2025.114556
Longfei Xiao , Yang Wang , Jinyan Hu , Zhongda Zhu , Xiaodi Ma , Hongjing Dou , Bijiang Geng , Dengyu Pan , Longxiang Shen
The high-efficiency treatment of infected bone defects necessitates the concurrent antibacterial and osteogenic activities of biocompatible scaffold materials. However, traditional clinical treatment modalities frequently suffer from antibiotic resistance, stubborn biofilm formation, and insufficient bone differentiation activity. Herein, we present a self-assembly strategy based on the coordination between Cu ions and Alendronate (ALN) to boost both antibacterial and osteogenic activities for the repair of infected bone defects. The self-assembly of ALN into a carrier-free drug delivery system can be induced by Cu ions, not only endowing ALN with excellent sonodynamic and chemodynamic activities for high-efficiency antibacterial therapy but also resulting in improved bioavailability and avoiding the possible carrier dilemma of low loading efficiency and poor stability. Moreover, Cu/ALN nanoneedles can selectively release Cu+, Cu2+, and ALN in bacterial microenvironment (BME) by breaking the Cu-N/Cu-O coordination bond under acidic conditions. The presence of Cu2+ in Cu/ALN provides effective glutathione peroxidase (GSH-px)-mimic catalytic activity for depleting glutathione (GSH) in BME, thereby avoiding the consumption of chemodynamic therapy (CDT)-generated reactive oxygen species (ROS) and achieving cascade amplification of ROS generation. Finally, the injectable Cu/ALN/GelMA hydrogels are fabricated through a single-step photochemical crosslinking process to examine the in vivo antibacterial efficacy and bone-regenerative potential of Cu/ALN. As a result, Cu/ALN-incorporated Gelatin Methacryloyl (GelMA) hydrogels significantly promote the healing of infected bone defects after implanting for one month through the ALN-facilitated osteogenic differentiation and Cu-ion-mediated cascade amplification of antibacterial activity. Overall, this work presents a novel perspective on the self-assembly multifunctional nanoplatforms with concurrent antibacterial and osteogenic activities for the treatment of infected bone defects.
高效治疗感染性骨缺损需要生物相容性支架材料同时具有抗菌和成骨活性。然而，传统的临床治疗方式往往存在抗生素耐药性、顽固的生物膜形成和骨分化活性不足等问题。在此，我们提出了一种基于Cu离子和阿仑膦酸钠（ALN）之间协调的自组装策略，以提高抗菌和成骨活性，从而修复受感染的骨缺陷。Cu离子可诱导ALN自组装成无载体给药系统，不仅使ALN具有良好的声动力学和化学动力学活性，可用于高效抗菌治疗，而且提高了ALN的生物利用度，避免了可能出现的载药效率低、稳定性差的载体困境。此外，Cu/ALN纳米针可以在酸性条件下通过破坏Cu- n /Cu- o配位键，选择性释放细菌微环境（BME）中的Cu+、Cu2+和ALN。Cu/ALN中Cu2+的存在提供了有效的谷胱甘肽过氧化物酶（GSH-px）模拟催化活性，以消耗BME中的谷胱甘肽（GSH），从而避免了化学动力学治疗（CDT）产生的活性氧（ROS）的消耗，并实现了ROS生成的级联扩增。最后，通过单步光化学交联法制备可注射Cu/ALN/GelMA水凝胶，考察Cu/ALN的体内抗菌效果和骨再生潜力。结果表明，加入Cu/ aln的明胶甲基丙烯酰（GelMA）水凝胶通过aln促进成骨分化和Cu离子介导的级联扩增抗菌活性，显著促进了植入一个月后感染骨缺损的愈合。总的来说，这项工作为自组装多功能纳米平台提供了一个新的视角，该平台具有抗菌和成骨活性，可用于治疗感染性骨缺陷。
{"title":"Self-assembled Cu-alendronate nanoneedle sonozymes promoting infected bone regeneration via synergistic sonodynamic and chemodynamic therapy","authors":"Longfei Xiao , Yang Wang , Jinyan Hu , Zhongda Zhu , Xiaodi Ma , Hongjing Dou , Bijiang Geng , Dengyu Pan , Longxiang Shen","doi":"10.1016/j.jconrel.2025.114556","DOIUrl":"10.1016/j.jconrel.2025.114556","url":null,"abstract":"<div><div>The high-efficiency treatment of infected bone defects necessitates the concurrent antibacterial and osteogenic activities of biocompatible scaffold materials. However, traditional clinical treatment modalities frequently suffer from antibiotic resistance, stubborn biofilm formation, and insufficient bone differentiation activity. Herein, we present a self-assembly strategy based on the coordination between Cu ions and Alendronate (ALN) to boost both antibacterial and osteogenic activities for the repair of infected bone defects. The self-assembly of ALN into a carrier-free drug delivery system can be induced by Cu ions, not only endowing ALN with excellent sonodynamic and chemodynamic activities for high-efficiency antibacterial therapy but also resulting in improved bioavailability and avoiding the possible carrier dilemma of low loading efficiency and poor stability. Moreover, Cu/ALN nanoneedles can selectively release Cu<sup>+</sup>, Cu<sup>2+</sup>, and ALN in bacterial microenvironment (BME) by breaking the Cu-N/Cu-O coordination bond under acidic conditions. The presence of Cu<sup>2+</sup> in Cu/ALN provides effective glutathione peroxidase (GSH-px)-mimic catalytic activity for depleting glutathione (GSH) in BME, thereby avoiding the consumption of chemodynamic therapy (CDT)-generated reactive oxygen species (ROS) and achieving cascade amplification of ROS generation. Finally, the injectable Cu/ALN/GelMA hydrogels are fabricated through a single-step photochemical crosslinking process to examine the in vivo antibacterial efficacy and bone-regenerative potential of Cu/ALN. As a result, Cu/ALN-incorporated Gelatin Methacryloyl (GelMA) hydrogels significantly promote the healing of infected bone defects after implanting for one month through the ALN-facilitated osteogenic differentiation and Cu-ion-mediated cascade amplification of antibacterial activity. Overall, this work presents a novel perspective on the self-assembly multifunctional nanoplatforms with concurrent antibacterial and osteogenic activities for the treatment of infected bone defects.</div></div>","PeriodicalId":15450,"journal":{"name":"Journal of Controlled Release","volume":"390 ","pages":"Article 114556"},"PeriodicalIF":11.5,"publicationDate":"2025-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145771266","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 : 2025-12-17DOI: 10.1016/j.jconrel.2025.114555
Yiling Yang , Xuejiao Zeng , Jingyan Wang , Jiaming Wang , Li Xie , Jinjin Shi , Wenyan Yu , Yan Zhang
Pulmonary delivery for idiopathic pulmonary fibrosis (IPF) remains limited by two major barriers: the mucus layer and macrophage-mediated drug sequestration. Here, we report an inhalable nanosystem that transforms these macrophages—from barriers—into active carriers for targeted delivery of interleukin-11 (IL-11) antisense oligonucleotides (ASO). The nanosystem is efficiently internalized by alveolar macrophages, allowing it to traverse the mucus barrier through macrophage migration. Once internalized, it facilitates lysosomal escape via the proton sponge effect and releases IL-11 ASOs in response to elevated reactive oxygen species. Incorporation of EV-sorting motifs enables nearly 80 % of ASOs to be packaged into macrophage-derived EVs, thereby promoting targeted offloading within fibrotic regions. This EV-mediated transcellular delivery enhances ASO accumulation in fibroblasts by fourfold and suppresses IL-11 expression by sixfold. Collectively, this macrophage-assisted delivery platform effectively overcomes both mucus and cellular barriers, offering a promising therapeutic strategy for IPF.
{"title":"Inhalable nanosystem promote in situ packaging of IL-11 antisense oligonucleotides into macrophage-derived vesicles for idiopathic pulmonary fibrosis","authors":"Yiling Yang , Xuejiao Zeng , Jingyan Wang , Jiaming Wang , Li Xie , Jinjin Shi , Wenyan Yu , Yan Zhang","doi":"10.1016/j.jconrel.2025.114555","DOIUrl":"10.1016/j.jconrel.2025.114555","url":null,"abstract":"<div><div>Pulmonary delivery for idiopathic pulmonary fibrosis (IPF) remains limited by two major barriers: the mucus layer and macrophage-mediated drug sequestration. Here, we report an inhalable nanosystem that transforms these macrophages—from barriers—into active carriers for targeted delivery of interleukin-11 (IL-11) antisense oligonucleotides (ASO). The nanosystem is efficiently internalized by alveolar macrophages, allowing it to traverse the mucus barrier through macrophage migration. Once internalized, it facilitates lysosomal escape via the proton sponge effect and releases IL-11 ASOs in response to elevated reactive oxygen species. Incorporation of EV-sorting motifs enables nearly 80 % of ASOs to be packaged into macrophage-derived EVs, thereby promoting targeted offloading within fibrotic regions. This EV-mediated transcellular delivery enhances ASO accumulation in fibroblasts by fourfold and suppresses IL-11 expression by sixfold. Collectively, this macrophage-assisted delivery platform effectively overcomes both mucus and cellular barriers, offering a promising therapeutic strategy for IPF.</div></div>","PeriodicalId":15450,"journal":{"name":"Journal of Controlled Release","volume":"390 ","pages":"Article 114555"},"PeriodicalIF":11.5,"publicationDate":"2025-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145784481","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 : 2025-12-17DOI: 10.1016/j.jconrel.2025.114554
Yuewen Zhu , Jiachen Li , Samin Abbaszadeh , Fatemeh Ghorbani-Bidkorpeh , Gésinda Geertsema-Doornbusch , Idaira Pacheco-Fernández , Raquel Bártolo , Marc C.A. Stuart , Wenguo Cui , Hélder A. Santos , Mohammad-Ali Shahbazi
Wound healing remains a major clinical challenge, as hypoxia, oxidative stress, and immune dysregulation collectively impede tissue regeneration. To overcome these multifactorial barriers, we developed an injectable hydrogel (FH-PMC-T) by integrating multifunctional PDA@MnO2@CuO (PMC) nanoparticles and taurine into a Fe3+ crosslinked Farsi gum–hyaluronic acid (FH) network. The hydrogel exhibits excellent photothermal conversion efficiency, catalase-like activity, and antioxidant capacity, enabling synergistic redox modulation and immune microenvironment regulation. Taurine is responsively released under high reactive oxygen species (ROS) conditions, contributing to the attenuation of inflammation and the suppression of macrophages M1 phenotype polarization. Moreover, the near-infrared (NIR)-responsive property allows mild photothermal therapy (PTT) to further stimulate fibroblast migration and tissue remodeling. In vivo, FH-PMC-T combined with NIR irradiation accelerates wound closure and enhances both structural and functional skin regeneration. This study proposes a hybrid photothermal–immunoregulatory hydrogel that orchestrates oxygenation, redox balance, and immune modulation for accelerated and restorative wound repair.
{"title":"Combined M1 macrophage inhibition and thermotherapy for controlled fibroplasia and accelerated wound repair via an oxygenating ROS-responsive hydrogel","authors":"Yuewen Zhu , Jiachen Li , Samin Abbaszadeh , Fatemeh Ghorbani-Bidkorpeh , Gésinda Geertsema-Doornbusch , Idaira Pacheco-Fernández , Raquel Bártolo , Marc C.A. Stuart , Wenguo Cui , Hélder A. Santos , Mohammad-Ali Shahbazi","doi":"10.1016/j.jconrel.2025.114554","DOIUrl":"10.1016/j.jconrel.2025.114554","url":null,"abstract":"<div><div>Wound healing remains a major clinical challenge, as hypoxia, oxidative stress, and immune dysregulation collectively impede tissue regeneration. To overcome these multifactorial barriers, we developed an injectable hydrogel (FH-PMC-T) by integrating multifunctional PDA@MnO<sub>2</sub>@CuO (PMC) nanoparticles and taurine into a Fe<sup>3+</sup> crosslinked Farsi gum–hyaluronic acid (FH) network. The hydrogel exhibits excellent photothermal conversion efficiency, catalase-like activity, and antioxidant capacity, enabling synergistic redox modulation and immune microenvironment regulation. Taurine is responsively released under high reactive oxygen species (ROS) conditions, contributing to the attenuation of inflammation and the suppression of macrophages M1 phenotype polarization. Moreover, the near-infrared (NIR)-responsive property allows mild photothermal therapy (PTT) to further stimulate fibroblast migration and tissue remodeling. In vivo, FH-PMC-T combined with NIR irradiation accelerates wound closure and enhances both structural and functional skin regeneration. This study proposes a hybrid photothermal–immunoregulatory hydrogel that orchestrates oxygenation, redox balance, and immune modulation for accelerated and restorative wound repair.</div></div>","PeriodicalId":15450,"journal":{"name":"Journal of Controlled Release","volume":"390 ","pages":"Article 114554"},"PeriodicalIF":11.5,"publicationDate":"2025-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145784480","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 : 2025-12-16DOI: 10.1016/j.jconrel.2025.114553
Kabirat T. Babalola , Raghu Ganugula , Meenakshi Arora , David Anderson , Sandeep K. Agarwal , Chandra Mohan , Babak J. Mehrara , M.N.V. Ravi Kumar
Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by immune dysregulation, systemic inflammation, and vascular complications. Cyclosporine A (CsA) is a potent immunosuppressant, but its systemic toxicity often limits its clinical use. To address this, we developed a lymph node-targeting nanoparticle formulation of CsA (P2Ns-GA-CsA) designed for CD71-mediated uptake to improve therapeutic efficacy while minimizing off-target effects. We conducted a preclinical dose optimization study in the MRL-lpr mouse model of lupus to define the effective therapeutic window of P2Ns-GA-CsA. Our preclinical dose optimization revealed a complex, biphasic immunological response. While all doses (5, 10, and 15 mg/kg) reduced inflammatory cytokines and kidney injury markers, a nuanced effect on immune activation was observed. The 5 mg/kg and 10 mg/kg doses successfully suppressed lymphocyte proliferation and immune activation, which was evident from reduced splenomegaly, lymphadenopathy, and plasma levels of anti-dsDNA and total IgG. Conversely, the 15 mg/kg dose paradoxically triggered immune hyperactivation, leading to aggressive lymphadenopathy, splenomegaly, and elevated autoantibodies. Mechanistically, the optimal 10 mg/kg dose downregulated key mediators of inflammation-induced lymphangiogenesis, corrected gut microbial dysbiosis, and restored microbiome-mediated tryptophan catabolism, contributing to systemic immunomodulation. These findings highlight the critical importance of non-regulatory dose optimization for nanomedicines, revealing complex pharmacodynamic responses often missed in conventional single-dose studies. Our results not only establish the targeted delivery of CsA as a viable therapeutic strategy for managing the vascular complications of SLE but also provide a crucial framework for ensuring the safety and efficacy of other repurposed immunomodulatory drugs in autoimmune diseases.
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Pub Date : 2025-12-16DOI: 10.1016/S0168-3659(25)01145-9
{"title":"Inside Back Cover_W. Zhang et al.","authors":"","doi":"10.1016/S0168-3659(25)01145-9","DOIUrl":"10.1016/S0168-3659(25)01145-9","url":null,"abstract":"","PeriodicalId":15450,"journal":{"name":"Journal of Controlled Release","volume":"389 ","pages":"Article 114531"},"PeriodicalIF":11.5,"publicationDate":"2025-12-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145784483","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 : 2025-12-16DOI: 10.1016/S0168-3659(25)01144-7
{"title":"Content list including Graphcal Abstracts","authors":"","doi":"10.1016/S0168-3659(25)01144-7","DOIUrl":"10.1016/S0168-3659(25)01144-7","url":null,"abstract":"","PeriodicalId":15450,"journal":{"name":"Journal of Controlled Release","volume":"389 ","pages":"Article 114530"},"PeriodicalIF":11.5,"publicationDate":"2025-12-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145784486","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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