Pub Date : 2026-01-03DOI: 10.1016/j.jconrel.2025.114599
Yang Chen , Jiao Ye , Yaling Wang, Hang Yang, Yan Wan, Qingcan Li, Bo Hu, Huijuan Jin
Ischemic stroke remains a major global health burden with limited treatment options, primarily due to the blood-brain barrier (BBB) impeding effective drug delivery. The neutrophil-targeted nanodrug delivery system emerges as a promising solution. By integrating the natural inflammatory tropism and BBB-penetrating ability of neutrophils with the precise drug-loading and controlled-release capabilities of nanotechnology, this system can efficiently transport drugs to ischemic brain regions. This paper first reviews clinically applied nanoparticles (NPs) for ischemic stroke therapy, then explores strategies for integrating NPs with neutrophils—including binding approaches and design considerations—shedding light on their transformative potential in enhancing drug penetration across the BBB and targeting ischemic foci for enrichment. In summary, existing literature highlights drug delivery as a major therapeutic hurdle in ischemic stroke. While neutrophils hold significant promise for advancing the clinical application of nanotechnology in this field, further research, technological refinements, and accelerated clinical translation remain essential to realize its full clinical value.
{"title":"Neutrophil-targeted nanomedicine for ischemic stroke therapy","authors":"Yang Chen , Jiao Ye , Yaling Wang, Hang Yang, Yan Wan, Qingcan Li, Bo Hu, Huijuan Jin","doi":"10.1016/j.jconrel.2025.114599","DOIUrl":"10.1016/j.jconrel.2025.114599","url":null,"abstract":"<div><div>Ischemic stroke remains a major global health burden with limited treatment options, primarily due to the blood-brain barrier (BBB) impeding effective drug delivery. The neutrophil-targeted nanodrug delivery system emerges as a promising solution. By integrating the natural inflammatory tropism and BBB-penetrating ability of neutrophils with the precise drug-loading and controlled-release capabilities of nanotechnology, this system can efficiently transport drugs to ischemic brain regions. This paper first reviews clinically applied nanoparticles (NPs) for ischemic stroke therapy, then explores strategies for integrating NPs with neutrophils—including binding approaches and design considerations—shedding light on their transformative potential in enhancing drug penetration across the BBB and targeting ischemic foci for enrichment. In summary, existing literature highlights drug delivery as a major therapeutic hurdle in ischemic stroke. While neutrophils hold significant promise for advancing the clinical application of nanotechnology in this field, further research, technological refinements, and accelerated clinical translation remain essential to realize its full clinical value.</div></div>","PeriodicalId":15450,"journal":{"name":"Journal of Controlled Release","volume":"391 ","pages":"Article 114599"},"PeriodicalIF":11.5,"publicationDate":"2026-01-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145893925","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 : 2026-01-03DOI: 10.1016/j.jconrel.2026.114602
Eugene Cheong, D. Christopher Radford, Adam J. Gormley
Hydrogels are widely used in drug delivery due to their biocompatibility and tunable release properties. However, optimizing hydrogel formulations to the desired release of therapeutics remains experimentally intensive. In this study, we developed an automated, high-throughput and machine learning (ML)-guided framework to efficiently optimize alginate formulations for drug delivery. Using a liquid handling robot, we initially prepared a diverse seed library of 120 alginate hydrogel formulations loaded with bovine serum albumin (BSA) and measured their release profiles. A Gaussian process regression (GPR) ML model was trained to predict cumulative release across time, enabling implicit modeling of release curves. Feature importance analysis using Shapley additive explanations (SHAP) identified time, alginate molecular weight, and concentration as dominant factors influencing release kinetics. Through Bayesian optimization and active learning, we iteratively selected and tested new formulations, progressively reaching a near zero-order release. Finally, the top-performing BSA-optimized formulations were directly applied to the sustained release of chondroitinase ABC single-enzyme nanoparticles (chABC-SENs), achieving near-zero-order release with no further optimizations. This study demonstrates a scalable, data-driven strategy for hydrogel formulation optimization and highlights the potential of ML to accelerate the development of controlled release systems for sensitive and valuable therapeutics.
{"title":"Automated active learning to optimize hydrogel drug release profiles","authors":"Eugene Cheong, D. Christopher Radford, Adam J. Gormley","doi":"10.1016/j.jconrel.2026.114602","DOIUrl":"10.1016/j.jconrel.2026.114602","url":null,"abstract":"<div><div>Hydrogels are widely used in drug delivery due to their biocompatibility and tunable release properties. However, optimizing hydrogel formulations to the desired release of therapeutics remains experimentally intensive. In this study, we developed an automated, high-throughput and machine learning (ML)-guided framework to efficiently optimize alginate formulations for drug delivery. Using a liquid handling robot, we initially prepared a diverse seed library of 120 alginate hydrogel formulations loaded with bovine serum albumin (BSA) and measured their release profiles. A Gaussian process regression (GPR) ML model was trained to predict cumulative release across time, enabling implicit modeling of release curves. Feature importance analysis using Shapley additive explanations (SHAP) identified time, alginate molecular weight, and concentration as dominant factors influencing release kinetics. Through Bayesian optimization and active learning, we iteratively selected and tested new formulations, progressively reaching a near zero-order release. Finally, the top-performing BSA-optimized formulations were directly applied to the sustained release of chondroitinase ABC single-enzyme nanoparticles (chABC-SENs), achieving near-zero-order release with no further optimizations. This study demonstrates a scalable, data-driven strategy for hydrogel formulation optimization and highlights the potential of ML to accelerate the development of controlled release systems for sensitive and valuable therapeutics.</div></div>","PeriodicalId":15450,"journal":{"name":"Journal of Controlled Release","volume":"391 ","pages":"Article 114602"},"PeriodicalIF":11.5,"publicationDate":"2026-01-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145895610","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 : 2026-01-02DOI: 10.1016/j.jconrel.2026.114600
Mingzhi Su , Yanwen Zhang , Zeen Lv , Weixin Zheng , Ningxi Hong , Fang Zheng , Ke Yao , Haijie Han , Yin Wang , Panpan Ye
Dry eye disease (DED) is a prevalent ocular surface disorder in which current therapies fail to achieve complete symptomatic relief. Given the pivotal role of excessive reactive oxygen species (ROS) in the vicious cycle of DED, effective strategies for ROS elimination remain urgently needed. Herein, a superoxide anion (O2·−)-responsive persulfide prodrug, Ac-SOPD, is designed for DED treatment. This prodrug specifically responses to O2·− to generate persulfides, which subsequently react with cysteine to trigger sustained hydrogen sulfide (H2S) release. The released H2S, a critical gasotransmitter, further scavenges residual ROS and bolsters endogenous antioxidant defenses. Mechanistically, Ac-SOPD efficiently eliminates excessive ROS, rejuvenates mitochondrial function, and inhibits the overactivation of the Hippo pathway, thereby preventing apoptosis. In both evaporative and aqueous-deficient DED models, Ac-SOPD significantly reduces oxidative stress, inflammation, and apoptosis on the ocular surface, thus alleviating corneal epithelial damage and improving tear film stability. Collectively, our findings demonstrate that Ac-SOPD holds strong potential for the treatment of DED and other oxidative stress-related diseases.
{"title":"A superoxide anion-responsive persulfide prodrug for remedying dry eye disease","authors":"Mingzhi Su , Yanwen Zhang , Zeen Lv , Weixin Zheng , Ningxi Hong , Fang Zheng , Ke Yao , Haijie Han , Yin Wang , Panpan Ye","doi":"10.1016/j.jconrel.2026.114600","DOIUrl":"10.1016/j.jconrel.2026.114600","url":null,"abstract":"<div><div>Dry eye disease (DED) is a prevalent ocular surface disorder in which current therapies fail to achieve complete symptomatic relief. Given the pivotal role of excessive reactive oxygen species (ROS) in the vicious cycle of DED, effective strategies for ROS elimination remain urgently needed. Herein, a superoxide anion (O<sub>2</sub>·<sup>−</sup>)-responsive persulfide prodrug, Ac-SOPD, is designed for DED treatment. This prodrug specifically responses to O<sub>2</sub>·<sup>−</sup> to generate persulfides, which subsequently react with cysteine to trigger sustained hydrogen sulfide (H<sub>2</sub>S) release. The released H<sub>2</sub>S, a critical gasotransmitter, further scavenges residual ROS and bolsters endogenous antioxidant defenses. Mechanistically, Ac-SOPD efficiently eliminates excessive ROS, rejuvenates mitochondrial function, and inhibits the overactivation of the Hippo pathway, thereby preventing apoptosis. In both evaporative and aqueous-deficient DED models, Ac-SOPD significantly reduces oxidative stress, inflammation, and apoptosis on the ocular surface, thus alleviating corneal epithelial damage and improving tear film stability. Collectively, our findings demonstrate that Ac-SOPD holds strong potential for the treatment of DED and other oxidative stress-related diseases.</div></div>","PeriodicalId":15450,"journal":{"name":"Journal of Controlled Release","volume":"391 ","pages":"Article 114600"},"PeriodicalIF":11.5,"publicationDate":"2026-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145893950","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 : 2026-01-02DOI: 10.1016/j.jconrel.2025.114593
Pi Zhao , Zhaokai Wang , Kedong Liu , Tong Wu , Jingyi Yang , Zixin Luo , Tianyu Zhang , Xingzhu Wang , Tao Wan
Lung cancer immunotherapy remains limited by the immunosuppressive tumor microenvironment (TME) and insufficient immunogenicity. Accumulating evidence indicates that tumor-derived exosomes (TDEs) play a pivotal role in shaping the immunosuppressive TME. Consequently, therapeutic strategies targeting TDE biogenesis and secretion offer a promising strategy to counteract tumor immune evasion. To this end, we developed an adenosine triphosphate (ATP)-responsive zeolitic imidazole framework-90 (ZIF-90)-based nanoplatform for the co-delivery of the exosome biosynthesis inhibitor GW4869 and the copper ionophore elesclomol (ES-Cu, a cuproptosis inducer). GW4869-mediated TDEs suppression alleviated immunosuppression and enhanced T-cell infiltration while simultaneously inducing reactive oxygen species (ROS) production to deplete glutathione (GSH). This GSH depletion potentiated ES-Cu-induced cuproptosis, and in combination with TDEs inhibition-mediated immunostimulation, established a positive feedback loop that remodels the TME to enhance antitumor immune responses. To our knowledge, this biomimetic nanoplatform presents an unexplored integration of exosome blockade with cuproptosis induction, establishing a novel paradigm for cancer immunotherapy.
{"title":"A self-amplifying cuproptosis nanomedicine to overcome immunosuppression by blocking tumor-derived exosomes for enhancing lung cancer immunotherapy","authors":"Pi Zhao , Zhaokai Wang , Kedong Liu , Tong Wu , Jingyi Yang , Zixin Luo , Tianyu Zhang , Xingzhu Wang , Tao Wan","doi":"10.1016/j.jconrel.2025.114593","DOIUrl":"10.1016/j.jconrel.2025.114593","url":null,"abstract":"<div><div>Lung cancer immunotherapy remains limited by the immunosuppressive tumor microenvironment (TME) and insufficient immunogenicity. Accumulating evidence indicates that tumor-derived exosomes (TDEs) play a pivotal role in shaping the immunosuppressive TME. Consequently, therapeutic strategies targeting TDE biogenesis and secretion offer a promising strategy to counteract tumor immune evasion. To this end, we developed an adenosine triphosphate (ATP)-responsive zeolitic imidazole framework-90 (ZIF-90)-based nanoplatform for the co-delivery of the exosome biosynthesis inhibitor GW4869 and the copper ionophore elesclomol (ES-Cu, a cuproptosis inducer). GW4869-mediated TDEs suppression alleviated immunosuppression and enhanced T-cell infiltration while simultaneously inducing reactive oxygen species (ROS) production to deplete glutathione (GSH). This GSH depletion potentiated ES-Cu-induced cuproptosis, and in combination with TDEs inhibition-mediated immunostimulation, established a positive feedback loop that remodels the TME to enhance antitumor immune responses. To our knowledge, this biomimetic nanoplatform presents an unexplored integration of exosome blockade with cuproptosis induction, establishing a novel paradigm for cancer immunotherapy.</div></div>","PeriodicalId":15450,"journal":{"name":"Journal of Controlled Release","volume":"391 ","pages":"Article 114593"},"PeriodicalIF":11.5,"publicationDate":"2026-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145893951","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 : 2026-01-02DOI: 10.1016/j.jconrel.2025.114596
Yanqiang Huang , Lei Lei , Lingli Huang , Wanping Yang , Chunyu Cong , Huizhen Xu , Guodong Wang , Jiazi Luo , Wenting Zhou , Ningyi Sun , Yi He , Min Dai , Shuyu Zhang , Biaoliang Wu , Haishi Qiao , Ke Ren
Cryptococcal meningitis is a life-threatening fungal infection of the central nervous system (CNS), characterized by an immunosuppressive microenvironment driven by Cryptococcus neoformans-induced polarization of macrophages toward M2 phenotype, which undermines host immunity and limits the efficacy of conventional antifungal therapies. To address these challenges, we developed a biomimetic mannose-modified nanovesicle (MBNV) system derived from Bacillus Calmette-Guérin (BCG)-primed bone marrow-derived macrophages (BMDMs) for dual action CNS immunotherapy. In vitro and in vivo studies demonstrate that MBNVs efficiently penetrate the blood-brain barrier (BBB), selectively accumulate within infected brain tissues, and specifically target M2-polarized macrophages via mannose receptor recognition. Upon delivery, MBNVs retain immunostimulatory cues from BCG-primed macrophages to effectively reprogram M2 macrophages toward a proinflammatory M1-like phenotype, thus restoring local antifungal immunity. As a proof of concept, we co-loaded the antifungal agent isobavachalcone (IBC) into MBNVs (IBC@MBNVs), achieving synergistic therapeutic effects in vivo. IBC@MBNVs significantly enhance macrophage repolarization, improve intracellular fungal clearance, markedly reduce CNS fungal burden, and extend survival in a murine cryptococcal meningitis model, surpassing the therapeutic efficacy of either component alone. This biomimetic dual functional strategy, integrating targeted immune reprogramming with CNS-targeted antifungal drug delivery, represents a promising and innovative approach to overcome immune evasion and drug delivery barriers in cryptococcal meningitis.
{"title":"A biomimetic nanovesicle derived from BCG-primed macrophages with mannose modification for targeted immunotherapy against cryptococcal meningitis","authors":"Yanqiang Huang , Lei Lei , Lingli Huang , Wanping Yang , Chunyu Cong , Huizhen Xu , Guodong Wang , Jiazi Luo , Wenting Zhou , Ningyi Sun , Yi He , Min Dai , Shuyu Zhang , Biaoliang Wu , Haishi Qiao , Ke Ren","doi":"10.1016/j.jconrel.2025.114596","DOIUrl":"10.1016/j.jconrel.2025.114596","url":null,"abstract":"<div><div>Cryptococcal meningitis is a life-threatening fungal infection of the central nervous system (CNS), characterized by an immunosuppressive microenvironment driven by <em>Cryptococcus neoformans</em>-induced polarization of macrophages toward M2 phenotype, which undermines host immunity and limits the efficacy of conventional antifungal therapies. To address these challenges, we developed a biomimetic mannose-modified nanovesicle (MBNV) system derived from Bacillus Calmette-Guérin (BCG)-primed bone marrow-derived macrophages (BMDMs) for dual action CNS immunotherapy. <em>In vitro</em> and <em>in vivo</em> studies demonstrate that MBNVs efficiently penetrate the blood-brain barrier (BBB), selectively accumulate within infected brain tissues, and specifically target M2-polarized macrophages <em>via</em> mannose receptor recognition. Upon delivery, MBNVs retain immunostimulatory cues from BCG-primed macrophages to effectively reprogram M2 macrophages toward a proinflammatory M1-like phenotype, thus restoring local antifungal immunity. As a proof of concept, we co-loaded the antifungal agent isobavachalcone (IBC) into MBNVs (IBC@MBNVs), achieving synergistic therapeutic effects <em>in vivo</em>. IBC@MBNVs significantly enhance macrophage repolarization, improve intracellular fungal clearance, markedly reduce CNS fungal burden, and extend survival in a murine cryptococcal meningitis model, surpassing the therapeutic efficacy of either component alone. This biomimetic dual functional strategy, integrating targeted immune reprogramming with CNS-targeted antifungal drug delivery, represents a promising and innovative approach to overcome immune evasion and drug delivery barriers in cryptococcal meningitis.</div></div>","PeriodicalId":15450,"journal":{"name":"Journal of Controlled Release","volume":"391 ","pages":"Article 114596"},"PeriodicalIF":11.5,"publicationDate":"2026-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145895612","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 : 2026-01-01DOI: 10.1016/j.jconrel.2025.114594
Qidong Tai , Haixing Feng , Yuan Tang , Yuyun Ye , Shuting Xie , Xikang Tang , Fei Peng , Xuefei Hu , Zhijin Fan , Yuhui Liao
Chronic diabetic wounds remain a formidable clinical challenge, largely attributed to persistent inflammation, excessive oxidative stress, and impaired angiogenesis. Current therapeutic approaches rarely integrate real-time infection monitoring with immunomodulation and tissue repair. Herein, we report an inflammation-responsive DNA hydrogel engineered with Lactobacillus reuteri-derived outer membrane vesicles (OMVs) and a self-reporting probe, enabling autonomous infection surveillance and on-demand therapeutic intervention. The hydrogel was constructed by crosslinking Y-shaped DNA motifs with disulfide-bridged linker strands conjugated to indocyanine green (ICG) and black hole quencher 3 (BHQ3), affording reactive oxygen species (ROS)-triggered signal activation and controlled OMV release. Benefiting from the intrinsic antioxidant and anti-apoptotic activities of OMVs, the hydrogel not only promoted keratinocyte migration, angiogenesis, and M2 macrophage polarization in vitro, but also delivered potent antibacterial activity under NIR light through fluorescence-guided photothermal therapy. In diabetic wound models, the system markedly accelerated closure by enhancing collagen deposition, neovascularization, and immune resolution while suppressing pro-inflammatory cytokine expression. Transcriptomic profiling further confirmed activation of regenerative pathways coupled with suppression of inflammatory cascades. Collectively, this multifunctional platform offer a paradigm shift for precision management of chronic wounds.
{"title":"Inflammation-responsive DNA hydrogel integrating probiotic outer membrane vesicles for infection monitoring and precision therapy of diabetic wounds","authors":"Qidong Tai , Haixing Feng , Yuan Tang , Yuyun Ye , Shuting Xie , Xikang Tang , Fei Peng , Xuefei Hu , Zhijin Fan , Yuhui Liao","doi":"10.1016/j.jconrel.2025.114594","DOIUrl":"10.1016/j.jconrel.2025.114594","url":null,"abstract":"<div><div>Chronic diabetic wounds remain a formidable clinical challenge, largely attributed to persistent inflammation, excessive oxidative stress, and impaired angiogenesis. Current therapeutic approaches rarely integrate real-time infection monitoring with immunomodulation and tissue repair. Herein, we report an inflammation-responsive DNA hydrogel engineered with <em>Lactobacillus reuteri</em>-derived outer membrane vesicles (OMVs) and a self-reporting probe, enabling autonomous infection surveillance and on-demand therapeutic intervention. The hydrogel was constructed by crosslinking Y-shaped DNA motifs with disulfide-bridged linker strands conjugated to indocyanine green (ICG) and black hole quencher 3 (BHQ3), affording reactive oxygen species (ROS)-triggered signal activation and controlled OMV release. Benefiting from the intrinsic antioxidant and anti-apoptotic activities of OMVs, the hydrogel not only promoted keratinocyte migration, angiogenesis, and M2 macrophage polarization in vitro, but also delivered potent antibacterial activity under NIR light through fluorescence-guided photothermal therapy. In diabetic wound models, the system markedly accelerated closure by enhancing collagen deposition, neovascularization, and immune resolution while suppressing pro-inflammatory cytokine expression. Transcriptomic profiling further confirmed activation of regenerative pathways coupled with suppression of inflammatory cascades. Collectively, this multifunctional platform offer a paradigm shift for precision management of chronic wounds.</div></div>","PeriodicalId":15450,"journal":{"name":"Journal of Controlled Release","volume":"391 ","pages":"Article 114594"},"PeriodicalIF":11.5,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145893952","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 : 2025-12-31DOI: 10.1016/j.jconrel.2025.114590
Manlin Qi , Yulin Xie , Jing Zhou , Chengyu Liu , Qihang Ding , Fanrou Zhang , Fangyu Shi , Biao Dong , Chunxia Li , Lin Wang
Chronic bacterial infections in diabetic wounds remain a major clinical challenge due to persistent inflammation, biofilm formation, and antibiotic resistance. Herein, we report a glucose-responsive cascade nanozyme system (PPCG) that functions as a microenvironment-adaptive reactive oxygen species (ROS) delivery platform for localized treatment of infected diabetic wounds. The PPCG integrates glucose oxidase (GOx) with a PdPtCu nanozyme core, enabling a triggered and self-sustaining catalytic cycle that amplifies ROS generation in glucose-rich infectious microenvironments while minimizing ROS release in glucose-deficient healthy tissue. GOx initiates the cascade by converting glucose into gluconic acid and H2O2. This locally generated H2O2 is then transformed into hydroxyl radicals via peroxidase- and glutathione oxidase-like activities, while catalase-like activity decomposes excess H2O2 into oxygen to reinforce the catalytic loop. Upon near-infrared-II laser irradiation, PPCG further enables synergistic photothermal disruption of bacterial biofilms. Multi-omics analyses revealed that PPCG triggers severe redox imbalance and metabolic stress, including impairing glucose uptake and glycolytic flux, triggering maladaptive carbon metabolic reprogramming, and ultimately resulting in ATP depletion and bacterial collapse. This spatiotemporally controlled ROS-generating platform represents a promising infection therapy that couples nanozyme cascade catalysis with metabolic targeting for enhanced bacterial eradication and minimal off-target effects.
{"title":"Glucose-responsive cascade nanozyme for controlled ROS release and bacterial carbon metabolic reprogramming in infected diabetic wounds","authors":"Manlin Qi , Yulin Xie , Jing Zhou , Chengyu Liu , Qihang Ding , Fanrou Zhang , Fangyu Shi , Biao Dong , Chunxia Li , Lin Wang","doi":"10.1016/j.jconrel.2025.114590","DOIUrl":"10.1016/j.jconrel.2025.114590","url":null,"abstract":"<div><div>Chronic bacterial infections in diabetic wounds remain a major clinical challenge due to persistent inflammation, biofilm formation, and antibiotic resistance. Herein, we report a glucose-responsive cascade nanozyme system (PPCG) that functions as a microenvironment-adaptive reactive oxygen species (ROS) delivery platform for localized treatment of infected diabetic wounds. The PPCG integrates glucose oxidase (GOx) with a PdPtCu nanozyme core, enabling a triggered and self-sustaining catalytic cycle that amplifies ROS generation in glucose-rich infectious microenvironments while minimizing ROS release in glucose-deficient healthy tissue. GOx initiates the cascade by converting glucose into gluconic acid and H<sub>2</sub>O<sub>2</sub>. This locally generated H<sub>2</sub>O<sub>2</sub> is then transformed into hydroxyl radicals via peroxidase- and glutathione oxidase-like activities, while catalase-like activity decomposes excess H<sub>2</sub>O<sub>2</sub> into oxygen to reinforce the catalytic loop. Upon near-infrared-II laser irradiation, PPCG further enables synergistic photothermal disruption of bacterial biofilms. Multi-omics analyses revealed that PPCG triggers severe redox imbalance and metabolic stress, including impairing glucose uptake and glycolytic flux, triggering maladaptive carbon metabolic reprogramming, and ultimately resulting in ATP depletion and bacterial collapse. This spatiotemporally controlled ROS-generating platform represents a promising infection therapy that couples nanozyme cascade catalysis with metabolic targeting for enhanced bacterial eradication and minimal off-target effects.</div></div>","PeriodicalId":15450,"journal":{"name":"Journal of Controlled Release","volume":"391 ","pages":"Article 114590"},"PeriodicalIF":11.5,"publicationDate":"2025-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145892539","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 : 2025-12-31DOI: 10.1016/j.jconrel.2025.114592
Chao Sun , Guanqing Yang , Tongtong Zhu , Shuqiang Li , Di Li , Jianxun Ding
In tumor microenvironments (TMEs), M1 macrophages suppress tumors through cytotoxic molecule secretion and antibody-dependent cell-mediated cytotoxicity, whereas M2 macrophages promote tumor proliferation via TGF-β and Arg1 release. However, existing macrophage-modulating strategies remain suboptimal owing to insufficient M2 suppression and inefficient M1 induction. To address this limitation, a multifunctional nanomedicine (PM-DPA/R848) is developed by loading the TLR7/8 agonist resiquimod (R848) into a nanocarrier composed of poly(L-methionine) (PM) and 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-poly(ethylene glycol)-alendronate (DSPE-PEG-ALN, DPA). The PM component reduces intracellular reactive oxygen species (ROS) levels in macrophages by 63.8%, resulting in a 31.1% reduction in M2-polarized macrophages compared with the Control group. Concurrently, R848 release induces M1 reprogramming through activation of the MYD88/IRAK1/NF-κB pathway, increasing the M1 macrophage population by 1.4-fold. Moreover, DPA enhances intratumoral drug accumulation in vivo, and PM-DPA/R848 achieves a 77% tumor suppression rate. Thus, PM-DPA/R848 acts as a precision nanoformulation that synergistically suppresses M2 macrophages and promotes M1 polarization, providing a promising strategy for osteosarcoma immunotherapy.
{"title":"Multifunctional poly(amino acid) nanomedicine modulates macrophage polarization for osteosarcoma immunotherapy","authors":"Chao Sun , Guanqing Yang , Tongtong Zhu , Shuqiang Li , Di Li , Jianxun Ding","doi":"10.1016/j.jconrel.2025.114592","DOIUrl":"10.1016/j.jconrel.2025.114592","url":null,"abstract":"<div><div>In tumor microenvironments (TMEs), M1 macrophages suppress tumors through cytotoxic molecule secretion and antibody-dependent cell-mediated cytotoxicity, whereas M2 macrophages promote tumor proliferation <em>via</em> TGF-β and Arg1 release. However, existing macrophage-modulating strategies remain suboptimal owing to insufficient M2 suppression and inefficient M1 induction. To address this limitation, a multifunctional nanomedicine (PM-DPA/R848) is developed by loading the TLR7/8 agonist resiquimod (R848) into a nanocarrier composed of poly(L-methionine) (PM) and 1,2-distearoyl-<em>sn</em>-glycero-3-phosphoethanolamine-<em>N</em>-poly(ethylene glycol)-alendronate (DSPE-PEG-ALN, DPA). The PM component reduces intracellular reactive oxygen species (ROS) levels in macrophages by 63.8%, resulting in a 31.1% reduction in M2-polarized macrophages compared with the Control group. Concurrently, R848 release induces M1 reprogramming through activation of the MYD88/IRAK1/NF-κB pathway, increasing the M1 macrophage population by 1.4-fold. Moreover, DPA enhances intratumoral drug accumulation <em>in vivo</em>, and PM-DPA/R848 achieves a 77% tumor suppression rate. Thus, PM-DPA/R848 acts as a precision nanoformulation that synergistically suppresses M2 macrophages and promotes M1 polarization, providing a promising strategy for osteosarcoma immunotherapy.</div></div>","PeriodicalId":15450,"journal":{"name":"Journal of Controlled Release","volume":"391 ","pages":"Article 114592"},"PeriodicalIF":11.5,"publicationDate":"2025-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145892575","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 : 2025-12-31DOI: 10.1016/j.jconrel.2025.114585
Jie-Wu Lin , Ching-Hsiang Fan , Tai-Tsung Kuo , Chih-Kuang Yeh
Focused ultrasound (FUS) can be combined with intravenously injected microbubbles (MBs) to transiently and noninvasively increase the permeability of the blood–brain barrier (BBB) to enable the targeted delivery of stem cells to the brain. Although this process has been demonstrated in animal models, several key issues remain unresolved: (1) whether vascular disruption enhances the delivery of stem cells beyond using BBB opening alone, (2) how the temporal sequence of stem-cell administration and BBB opening affects efficiency, (3) the relative contributions of BBB permeability and inflammation to stem-cell accumulation, and (4) the temporal distribution and persistence of stem cells after BBB opening. To address these questions, we first used an in vitro HUVEC (human umbilical vein endothelial cell) monolayer barrier model and red-fluorescent-protein–labeled cord-blood mesenchymal stem cells (MSCs) to evaluate the efficacy of delivering MSCs using 1-MHz FUS at 300–600 kPa with MBs. The optimal condition for increasing the endothelial barrier permeability was using FUS at 300 kPa, which induced a 1.3-fold reduction in the fluorescence intensity of the ZO-1 tight-junction protein at the cell borders (203 ± 4 μm gaps), while cell viability remained high (93.5 %) and the migration of MSCs increased 1.8–2.6-fold. We then established two in vivo BBB-opening conditions by fine-tuning the acoustic pressure: (1) safe opening with minimal inflammation and (2) opening with severe vascular disruption. We found that safe BBB opening achieved the efficient delivery of MSCs, and this was not increased by vascular disruption, which could even reduce the penetration of MSCs. Furthermore, FUS + MBs-mediated delivery preserved the intrinsic properties of MSCs and was safer than intracranial injection. The number of MSCs accumulating in the brain progressively increased to peak at 24 h after FUS sonication. These findings suggest that both BBB opening and inflammation contribute to MSC migration, with transient BBB opening enabling the rapid and efficient delivery of MSCs, whereas inflammation supports prolonged recruitment, maintaining MSC accumulation for up to 7 days.
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