Pub Date : 2026-02-09DOI: 10.1016/j.jconrel.2026.114685
Huai Yang, Jing-Long Hu, Yunjun Xu, Tian-Ci Sun, Xu Yan, Haojie Lu, Dongquan Liu, Baoqiang Cao, Yang Lu, Tao He
Percutaneous locoregional drug injection based on hydrogel therapy under image guidance is performed to limit the progression of hepatocellular carcinoma (HCC) and extend the waiting time for liver transplantation patients. However, achieving uniform distribution and sustained retention of drugs within the tumor bed remains a critical bottleneck urgently requiring breakthroughs in the current field of oncology. Here, an acid-labile thermosensitive hydrogel (denoted as NCD) with efficient magnetothermal functionality was developed by incorporating iron oxide nanoparticles (CION) and DOX into the ortho-ester-functionalized thermosensitive polymer matrix (poly(N-isopropylacrylamide270)-ortho ester-poly(ethylene glycol)). Engineered for multimodal therapy, the NCD hydrogel utilized an acid-cleavable backbone to achieve sustained DOX release (77.4 ± 2.1% at pH 6.5, 72 h), markedly exceeding the control release of 26.8 ± 2.7% and yielding uniform tumor drug distribution. Its thermosensitive PNIPAM matrix (LCST ≈ 32 °C) enabled injectable sol-gel transition at body temperature, allowing easy administration (maximum injection pressure: merely 6.0 ± 0.3 N) and forming a depot for prolonged drug retention. Combined with CION-enhanced magnetothermal therapy, ultrasound-guided NCD delivery suppressed orthotopic liver tumor growth, positioning it as a promising bridging strategy to transplantation.
{"title":"Injectable acid-labile thermosensitive magnetic hydrogel with responsive drug release for bridging liver transplantation in hepatocellular carcinoma","authors":"Huai Yang, Jing-Long Hu, Yunjun Xu, Tian-Ci Sun, Xu Yan, Haojie Lu, Dongquan Liu, Baoqiang Cao, Yang Lu, Tao He","doi":"10.1016/j.jconrel.2026.114685","DOIUrl":"https://doi.org/10.1016/j.jconrel.2026.114685","url":null,"abstract":"Percutaneous locoregional drug injection based on hydrogel therapy under image guidance is performed to limit the progression of hepatocellular carcinoma (HCC) and extend the waiting time for liver transplantation patients. However, achieving uniform distribution and sustained retention of drugs within the tumor bed remains a critical bottleneck urgently requiring breakthroughs in the current field of oncology. Here, an acid-labile thermosensitive hydrogel (denoted as NCD) with efficient magnetothermal functionality was developed by incorporating iron oxide nanoparticles (CION) and DOX into the ortho-ester-functionalized thermosensitive polymer matrix (poly(<ce:italic>N</ce:italic>-isopropylacrylamide<ce:inf loc=\"post\">270</ce:inf>)-ortho ester-poly(ethylene glycol)). Engineered for multimodal therapy, the NCD hydrogel utilized an acid-cleavable backbone to achieve sustained DOX release (77.4 ± 2.1% at pH 6.5, 72 h), markedly exceeding the control release of 26.8 ± 2.7% and yielding uniform tumor drug distribution. Its thermosensitive PNIPAM matrix (LCST ≈ 32 °C) enabled injectable sol-gel transition at body temperature, allowing easy administration (maximum injection pressure: merely 6.0 ± 0.3 N) and forming a depot for prolonged drug retention. Combined with CION-enhanced magnetothermal therapy, ultrasound-guided NCD delivery suppressed orthotopic liver tumor growth, positioning it as a promising bridging strategy to transplantation.","PeriodicalId":15450,"journal":{"name":"Journal of Controlled Release","volume":"89 1","pages":""},"PeriodicalIF":10.8,"publicationDate":"2026-02-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146146631","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}
Age-related nicotinamide adenine dinucleotide (NAD+) deficiency is implicated in numerous pathologies, including dry age-related macular degeneration (AMD). Current NAD+-boosting strategies, reliant on precursors like nicotinamide mononucleotide (NMN), necessitate repeated dosing and offer transient effects, limiting therapeutic utility. Here, we address this critical limitation by developing a single-dose therapy using circular mRNA (circ-mRNA) to deliver functional nicotinamide phosphoribosyl transferase (NAMPT), the essential rate-limiting enzyme in NAD+ salvage. Engineered via permuted intron-exon (PIE) splicing, our circNAMPT exploits the exceptional stability and persistent translation capacity inherent to circular RNA scaffolds. Encapsulation in β-sitosterol-optimized lipid nanoparticles (LNPs) ensures robust intracellular delivery. In vitro, circNAMPT-LNP drives sustained NAMPT expression and prolonged NAD+ elevation, circumventing precursor limitations. In a stringent sodium iodate-induced dry AMD model, a single intravitreal circNAMPT-LNP injection matched the neuroprotective efficacy of 14 consecutive daily intraperitoneal NMN doses confirmed by histological integrity and functional preservation. This work establishes engineered circ-mRNAs as a transformative platform for durable, single-dose therapeutic protein delivery, demonstrates potential as a disease-modifying therapy for dry AMD. Its applicability extends broadly to systemic disorders driven by NAD+ deficiency in aging.
{"title":"Single intravitreal injection of lipid nanoparticles delivering circular mRNA of nicotinamide phosphoribosyltransferase protects against dry AMD","authors":"Hui-Lin Li, Yu Xu, Jian-Shan Mo, Xin-Yuan Zhao, Cai-Ling Zhong, Zi-Wen Jia, Xiao-Long Wang, Ben-Chi Zhao, Yan-Ming Chen, Ke-Wei Zheng, Xiao-Lei Zhang, Qiao-Ping Wang","doi":"10.1016/j.jconrel.2026.114691","DOIUrl":"https://doi.org/10.1016/j.jconrel.2026.114691","url":null,"abstract":"Age-related nicotinamide adenine dinucleotide (NAD<sup>+</sup>) deficiency is implicated in numerous pathologies, including dry age-related macular degeneration (AMD). Current NAD<sup>+</sup>-boosting strategies, reliant on precursors like nicotinamide mononucleotide (NMN), necessitate repeated dosing and offer transient effects, limiting therapeutic utility. Here, we address this critical limitation by developing a single-dose therapy using circular mRNA (circ-mRNA) to deliver functional nicotinamide phosphoribosyl transferase (NAMPT), the essential rate-limiting enzyme in NAD<sup>+</sup> salvage. Engineered via permuted intron-exon (PIE) splicing, our circNAMPT exploits the exceptional stability and persistent translation capacity inherent to circular RNA scaffolds. Encapsulation in β-sitosterol-optimized lipid nanoparticles (LNPs) ensures robust intracellular delivery. In vitro, circNAMPT-LNP drives sustained NAMPT expression and prolonged NAD<sup>+</sup> elevation, circumventing precursor limitations. In a stringent sodium iodate-induced dry AMD model, a single intravitreal circNAMPT-LNP injection matched the neuroprotective efficacy of 14 consecutive daily intraperitoneal NMN doses confirmed by histological integrity and functional preservation. This work establishes engineered circ-mRNAs as a transformative platform for durable, single-dose therapeutic protein delivery, demonstrates potential as a disease-modifying therapy for dry AMD. Its applicability extends broadly to systemic disorders driven by NAD<sup>+</sup> deficiency in aging.","PeriodicalId":15450,"journal":{"name":"Journal of Controlled Release","volume":"568 1","pages":""},"PeriodicalIF":10.8,"publicationDate":"2026-02-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146138283","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}
Ionizable lipids enable lipid nanoparticles (LNPs) to deliver nucleic acids, including mRNA, to target cells. However, the efficiency of the endosomal escape of conventional LNPs remains limited to a small percentage. Lipid components that actively interact with net-neutral phospholipids in endosomal membranes and promote membrane fusion potentially enhance the efficiency of endosomal escape and further improve functional mRNA delivery. In this study, we developed a zwitterionic tri-oleoyl-Tris (zTOT) library and used it to enhance mRNA delivery by replacing the widely used helper lipid 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC) in LNPs with zTOT. LNPs containing TOT-15, an example of zTOT, demonstrated a 5-fold higher gene expression compared with that of DSPC-LNPs. TOT-15-LNPs composed of commercially available ionizable lipids showed enhanced gene expression compared with that of DSPC-LNPs. The TOT-15-LNPs also showed almost 100% gene knockout efficiency with no toxicity. The TOT-15 system interacts with 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) and induces a non-lamellar structure. Pharmacokinetic calculation revealed that endosomal escape efficiency of the TOT-15-LNPs was more than 9.6%. In summary, the results of this study demonstrate that the zTOT system enhances the efficiency of both endosomal escape and functional mRNA delivery.
可电离脂质使脂质纳米颗粒（LNPs）能够将核酸（包括mRNA）递送到靶细胞。然而，传统LNPs的内体逃逸效率仍然局限于很小的百分比。与内体膜中净中性磷脂积极相互作用并促进膜融合的脂质成分可能提高内体逃逸效率并进一步改善mRNA的功能性传递。在这项研究中，我们建立了一个两性离子三油酰三（zTOT）文库，并用zTOT取代LNPs中广泛使用的辅助脂质1,2-二硬脂酰- san -甘油-3-磷酸胆碱（dsc）来增强mRNA的传递。以zTOT为例，含有TOT-15的LNPs的基因表达量比含有DSPC-LNPs的LNPs高5倍。由市售可电离脂质组成的TOT-15-LNPs与DSPC-LNPs相比，基因表达增强。TOT-15-LNPs也显示出几乎100%的基因敲除效率，而且没有毒性。TOT-15体系与1-棕榈酰-2-油基- cn -甘油-3-磷酸胆碱（POPC）相互作用，诱导出非层状结构。药代动力学计算表明，TOT-15-LNPs的内体逃逸效率大于9.6%。总之，本研究的结果表明，zTOT系统提高了内体逃逸和功能性mRNA传递的效率。
{"title":"Lipid nanoparticles containing zwitterionic lipids versatilely enhance the efficiency of mRNA delivery","authors":"Yuichi Suzuki , Yuma Yamada , Hideyoshi Harashima , Yusuke Sato","doi":"10.1016/j.jconrel.2026.114709","DOIUrl":"10.1016/j.jconrel.2026.114709","url":null,"abstract":"<div><div>Ionizable lipids enable lipid nanoparticles (LNPs) to deliver nucleic acids, including mRNA, to target cells. However, the efficiency of the endosomal escape of conventional LNPs remains limited to a small percentage. Lipid components that actively interact with net-neutral phospholipids in endosomal membranes and promote membrane fusion potentially enhance the efficiency of endosomal escape and further improve functional mRNA delivery. In this study, we developed a zwitterionic tri-oleoyl-Tris (zTOT) library and used it to enhance mRNA delivery by replacing the widely used helper lipid 1,2-distearoyl-<em>sn</em>-glycero-3-phosphocholine (DSPC) in LNPs with zTOT. LNPs containing TOT-15, an example of zTOT, demonstrated a 5-fold higher gene expression compared with that of DSPC-LNPs. TOT-15-LNPs composed of commercially available ionizable lipids showed enhanced gene expression compared with that of DSPC-LNPs. The TOT-15-LNPs also showed almost 100% gene knockout efficiency with no toxicity. The TOT-15 system interacts with 1-palmitoyl-2-oleoyl-<em>sn</em>-glycero-3-phosphocholine (POPC) and induces a non-lamellar structure. Pharmacokinetic calculation revealed that endosomal escape efficiency of the TOT-15-LNPs was more than 9.6%. In summary, the results of this study demonstrate that the zTOT system enhances the efficiency of both endosomal escape and functional mRNA delivery.</div></div>","PeriodicalId":15450,"journal":{"name":"Journal of Controlled Release","volume":"392 ","pages":"Article 114709"},"PeriodicalIF":11.5,"publicationDate":"2026-02-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146146644","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 : 2026-02-08DOI: 10.1016/j.jconrel.2026.114706
Hai Huang , Wenjie Xu , Xinyan Hao , Pengcheng Sun , Mengen Guo , Muyan Li , Xinying Liu , Yanjin Peng , Ruyue Han , Tiantian Tang , Yucheng Tang , Daxiong Xiang , Ming Wang , Junyong Wu
Extracellular vesicles (EVs) are now seen as powerful tools for next-generation diagnostics, targeted drug delivery, and cell-free therapies. Their clinical application, however, is constrained by storage challenges—the preservation process compromises their structure and activity. This review summarizes current methods for preserving EVs, including cryopreservation, spray-drying, and freeze-drying. It also discusses how suboptimal storage conditions affect the critical quality attributes (CQAs) of EVs, including membrane integrity, cargo stability, biological activity, immunogenicity, and recovery efficiency. This review adopts an application-oriented approach, highlighting the distinct stability requirements for EVs serving as diagnostic markers, delivery vehicles, or therapeutic agents. Furthermore, it also evaluated new optimization strategies, such as a reasonable cryopreservation protective agent formulation, an improved buffer solution formulation, reduced adsorption storage materials, and advanced material-based stable technologies. Finally, this review outlines the future directions, emphasizing the need to adopt standardized and scalable preservation methods that are oriented towards EV clinical applications, to accelerate the transition of EV-based technologies from the laboratory to clinical practice.
{"title":"A comprehensive review on the storage stability of extracellular vesicles for clinical translation: Current status, challenges, and prospects","authors":"Hai Huang , Wenjie Xu , Xinyan Hao , Pengcheng Sun , Mengen Guo , Muyan Li , Xinying Liu , Yanjin Peng , Ruyue Han , Tiantian Tang , Yucheng Tang , Daxiong Xiang , Ming Wang , Junyong Wu","doi":"10.1016/j.jconrel.2026.114706","DOIUrl":"10.1016/j.jconrel.2026.114706","url":null,"abstract":"<div><div>Extracellular vesicles (EVs) are now seen as powerful tools for next-generation diagnostics, targeted drug delivery, and cell-free therapies. Their clinical application, however, is constrained by storage challenges—the preservation process compromises their structure and activity. This review summarizes current methods for preserving EVs, including cryopreservation, spray-drying, and freeze-drying. It also discusses how suboptimal storage conditions affect the critical quality attributes (CQAs) of EVs, including membrane integrity, cargo stability, biological activity, immunogenicity, and recovery efficiency. This review adopts an application-oriented approach, highlighting the distinct stability requirements for EVs serving as diagnostic markers, delivery vehicles, or therapeutic agents. Furthermore, it also evaluated new optimization strategies, such as a reasonable cryopreservation protective agent formulation, an improved buffer solution formulation, reduced adsorption storage materials, and advanced material-based stable technologies. Finally, this review outlines the future directions, emphasizing the need to adopt standardized and scalable preservation methods that are oriented towards EV clinical applications, to accelerate the transition of EV-based technologies from the laboratory to clinical practice.</div></div>","PeriodicalId":15450,"journal":{"name":"Journal of Controlled Release","volume":"392 ","pages":"Article 114706"},"PeriodicalIF":11.5,"publicationDate":"2026-02-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146134050","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 : 2026-02-07DOI: 10.1016/j.jconrel.2026.114700
Huiqi Zhang , Dong Luo , Guojun Cai , Manman Hu , Zhen Fan , Meng Li
Severe cutaneous injury predictably culminates in scar formation, typified by the loss of skin appendages and a consequent impairment of both structural integrity and physiological function. A growing body of evidence now indicates that mechanical cues are as determinative as biochemical signals in directing cutaneous repair and scar formation. Accordingly, mechanomodulatory biomaterials have emerged as promising platforms for promoting scar-free wound repair. However, the mechanistic bases by which mechanical forces remodel the extracellular milieu—and how such forces can be rationally exploited to reprogram mechanotransductive signaling—remain incompletely resolved. This knowledge gap poses a major barrier to the clinical translation of mechanotherapeutic approaches. In this review, we synthesize current understanding of cutaneous biomechanics and its intimate interplay with wound-healing cascades, and we delineate the principal mechanotransduction pathways that convert physical stimuli into cellular fate decisions. We further provide a critical appraisal of recent advances in mechanically active dressings designed to deliver spatially and temporally controlled mechanical cues that bias tissue repair toward regeneration. Finally, we identify outstanding challenges and propose future directions for the development of mechanoregulated biomaterials, offering a strategic roadmap to accelerate the translation of scarless healing strategies into clinical practice.
{"title":"Wound healing under the regulation of mechanically active biomaterials: From mechanism exploration to scar prevention","authors":"Huiqi Zhang , Dong Luo , Guojun Cai , Manman Hu , Zhen Fan , Meng Li","doi":"10.1016/j.jconrel.2026.114700","DOIUrl":"10.1016/j.jconrel.2026.114700","url":null,"abstract":"<div><div>Severe cutaneous injury predictably culminates in scar formation, typified by the loss of skin appendages and a consequent impairment of both structural integrity and physiological function. A growing body of evidence now indicates that mechanical cues are as determinative as biochemical signals in directing cutaneous repair and scar formation. Accordingly, mechanomodulatory biomaterials have emerged as promising platforms for promoting scar-free wound repair. However, the mechanistic bases by which mechanical forces remodel the extracellular milieu—and how such forces can be rationally exploited to reprogram mechanotransductive signaling—remain incompletely resolved. This knowledge gap poses a major barrier to the clinical translation of mechanotherapeutic approaches. In this review, we synthesize current understanding of cutaneous biomechanics and its intimate interplay with wound-healing cascades, and we delineate the principal mechanotransduction pathways that convert physical stimuli into cellular fate decisions. We further provide a critical appraisal of recent advances in mechanically active dressings designed to deliver spatially and temporally controlled mechanical cues that bias tissue repair toward regeneration. Finally, we identify outstanding challenges and propose future directions for the development of mechanoregulated biomaterials, offering a strategic roadmap to accelerate the translation of scarless healing strategies into clinical practice.</div></div>","PeriodicalId":15450,"journal":{"name":"Journal of Controlled Release","volume":"392 ","pages":"Article 114700"},"PeriodicalIF":11.5,"publicationDate":"2026-02-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146134058","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 : 2026-02-07DOI: 10.1016/j.jconrel.2026.114697
Bihui Cao , Manting Liu , Sainiwaer Anwaier , Xiang Long , Ting You , Zijian He , Haotao Su , Xinkui Zhang , Jiaqi Wang , Huanlei Huang , Nanbo Liu , Yujie Jiang , Hongmo Xiang , Yehuda G. Assaraf , Xiaolan Zhu , Xuelei Ma , Qi Zhao , Ping Zhu , Lu Wang
Cardiac fibrosis is a key pathological feature of both acute and chronic heart diseases, characterized by abnormal accumulation of extracellular matrix resulting from fibroblast activation. Although fibroblast activation protein (FAP)-targeted chimeric antigen receptor (CAR) T cell therapy has shown promise in selectively eliminating activated fibroblasts, systemic administration remains limited by off-target toxicity and insufficient trafficking to the diseased myocardium. Here, we present a reactive oxygen species (ROS)-responsive hydrogel designed for intrapericardial delivery of FAP-specific CAR-T (FAP-CAR-T) cells to locally treat post-myocardial infarction (MI) fibrosis. This hydrogel, based on a thioketal-crosslinked polyethylene glycol matrix, selectively degrades in the ROS-enriched microenvironment of fibrotic tissue, enabling the controlled release of encapsulated FAP-CAR-T cells. In vitro, FAP-CAR-T cells exhibited antigen-dependent cytotoxicity against FAP+ targets, and hydrogel-encapsulated CAR-T cells maintained robust proliferation and showed ROS-triggered release kinetics. Using murine models of MI-induced fibrosis, the hydrogel-based intrapericardial delivery strategy enhanced FAP-CAR-T cells infiltration, persistence, and effector function, resulting in significant depletion of activated fibroblasts, attenuation of fibrotic remodeling, and preservation of cardiac structure and left ventricular function. This hydrogel-based CAR-T immunotherapeutic platform provides a localized, targeted, and on-demand strategy for combating cardiac fibrosis and may offer broader translational potential for the treatment of fibrotic diseases.
{"title":"Intrapericardial delivery of FAP-CAR-T cells via a ROS-responsive hydrogel to treat cardiac fibrosis","authors":"Bihui Cao , Manting Liu , Sainiwaer Anwaier , Xiang Long , Ting You , Zijian He , Haotao Su , Xinkui Zhang , Jiaqi Wang , Huanlei Huang , Nanbo Liu , Yujie Jiang , Hongmo Xiang , Yehuda G. Assaraf , Xiaolan Zhu , Xuelei Ma , Qi Zhao , Ping Zhu , Lu Wang","doi":"10.1016/j.jconrel.2026.114697","DOIUrl":"10.1016/j.jconrel.2026.114697","url":null,"abstract":"<div><div>Cardiac fibrosis is a key pathological feature of both acute and chronic heart diseases, characterized by abnormal accumulation of extracellular matrix resulting from fibroblast activation. Although fibroblast activation protein (FAP)-targeted chimeric antigen receptor (CAR) T cell therapy has shown promise in selectively eliminating activated fibroblasts, systemic administration remains limited by off-target toxicity and insufficient trafficking to the diseased myocardium. Here, we present a reactive oxygen species (ROS)-responsive hydrogel designed for intrapericardial delivery of FAP-specific CAR-T (FAP-CAR-T) cells to locally treat post-myocardial infarction (MI) fibrosis. This hydrogel, based on a thioketal-crosslinked polyethylene glycol matrix, selectively degrades in the ROS-enriched microenvironment of fibrotic tissue, enabling the controlled release of encapsulated FAP-CAR-T cells. In vitro, FAP-CAR-T cells exhibited antigen-dependent cytotoxicity against FAP<sup>+</sup> targets, and hydrogel-encapsulated CAR-T cells maintained robust proliferation and showed ROS-triggered release kinetics. Using murine models of MI-induced fibrosis, the hydrogel-based intrapericardial delivery strategy enhanced FAP-CAR-T cells infiltration, persistence, and effector function, resulting in significant depletion of activated fibroblasts, attenuation of fibrotic remodeling, and preservation of cardiac structure and left ventricular function. This hydrogel-based CAR-T immunotherapeutic platform provides a localized, targeted, and on-demand strategy for combating cardiac fibrosis and may offer broader translational potential for the treatment of fibrotic diseases.</div></div>","PeriodicalId":15450,"journal":{"name":"Journal of Controlled Release","volume":"392 ","pages":"Article 114697"},"PeriodicalIF":11.5,"publicationDate":"2026-02-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146134054","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 : 2026-02-07DOI: 10.1016/j.jconrel.2026.114705
Emily L. DeWolf, Bernice Webber, Matthew J. Webber
Biologic therapies for diabetes have advanced significantly through molecular engineering strategies that optimize therapeutic stability, pharmacokinetics, and delivery. This review presents an integrated overview of design principles used to develop insulin, glucagon, amylin analogs, and GLP-1 receptor agonists, highlighting their unique physicochemical challenges and therapeutic requirements. Structural modifications—including amino acid substitutions, peptide stapling, glycosylation, and PEGylation—are discussed for their roles in enhancing stability, reducing aggregation, and extending half-life. Strategies for tuning pharmacokinetics are examined, ranging from sequence-driven solubility modulation to formulation-based depot formation and vascular binding mechanisms. Various administration routes, including oral, inhaled, and intranasal delivery, are evaluated for their potential to improve adherence and more closely mimic endogenous hormone profiles. The review also addresses the development of combination therapies and multi-receptor agonists designed to synergize complementary hormonal pathways. Finally, recent progress in glucose-responsive systems is reviewed, emphasizing molecular and materials-based approaches that enable real-time, glucose-triggered therapeutic activation. Taken together, the evolution of diabetes therapeutics exemplifies the application of core molecular design concepts in biologic drug development. The strategies outlined herein not only address the complex demands of glycemic control but also provide a broadly applicable framework for engineering next-generation protein-based therapies for applications beyond diabetes.
{"title":"Molecular engineering of designer diabetes therapeutics","authors":"Emily L. DeWolf, Bernice Webber, Matthew J. Webber","doi":"10.1016/j.jconrel.2026.114705","DOIUrl":"10.1016/j.jconrel.2026.114705","url":null,"abstract":"<div><div>Biologic therapies for diabetes have advanced significantly through molecular engineering strategies that optimize therapeutic stability, pharmacokinetics, and delivery. This review presents an integrated overview of design principles used to develop insulin, glucagon, amylin analogs, and GLP-1 receptor agonists, highlighting their unique physicochemical challenges and therapeutic requirements. Structural modifications—including amino acid substitutions, peptide stapling, glycosylation, and PEGylation—are discussed for their roles in enhancing stability, reducing aggregation, and extending half-life. Strategies for tuning pharmacokinetics are examined, ranging from sequence-driven solubility modulation to formulation-based depot formation and vascular binding mechanisms. Various administration routes, including oral, inhaled, and intranasal delivery, are evaluated for their potential to improve adherence and more closely mimic endogenous hormone profiles. The review also addresses the development of combination therapies and multi-receptor agonists designed to synergize complementary hormonal pathways. Finally, recent progress in glucose-responsive systems is reviewed, emphasizing molecular and materials-based approaches that enable real-time, glucose-triggered therapeutic activation. Taken together, the evolution of diabetes therapeutics exemplifies the application of core molecular design concepts in biologic drug development. The strategies outlined herein not only address the complex demands of glycemic control but also provide a broadly applicable framework for engineering next-generation protein-based therapies for applications beyond diabetes.</div></div>","PeriodicalId":15450,"journal":{"name":"Journal of Controlled Release","volume":"392 ","pages":"Article 114705"},"PeriodicalIF":11.5,"publicationDate":"2026-02-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146134056","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 : 2026-02-07DOI: 10.1016/j.jconrel.2026.114681
Yeshuang Yuan , Mengfan Yu , Xingxing Zhu , Wei Sun , Jing Li , Yiming Wang , Shanbo Yang , Yingying Shi , Zhaolin Wang , Xinyue Wang , Fudi Wang , Yue Xu , Min Wang , Jin Hu , Bo Zhang , Yudong Liu , Xuan Zhang
Current therapies for autoimmune diseases largely rely on broad-spectrum immunosuppressants and biologics, which indiscriminately deplete T or B cells. These approaches are largely constrained by systemic immunosuppression and off-target toxicities. Achieving durable, antigen-specific immune tolerance while preserving protective immunity against pathogens remains a long-standing goal in clinical practice. Here, we present a modular red blood cell (RBC)-based platform that induces antigen-specific tolerance through strain-promoted azide-alkyne cycloaddition (SPAAC)-mediated surface conjugation of disease-relevant peptides. We demonstrated that RBCs engineered by such approach retain their biophysical integrity and biocompatibility across a broad range of conjugation concentrations in vitro. Critically, when conjugated with single or multiple autoantigenic epitopes, these engineered RBCs elicited robust antigen-specific tolerance and drove durable disease remission in two well-established preclinical models, experimental autoimmune encephalomyelitis (EAE) and collagen-induced arthritis (CIA). Further mechanistic investigations revealed that the engineered RBCs reprogram antigen-presenting cells (APCs) toward a tolerogenic phenotype. This reprogramming, in turn, induces anergy in autoreactive T cells and suppresses the activation of autoreactive B cells. Collectively, this work establishes a versatile and clinically translatable platform, offering a path toward personalized, antigen-specific therapy for autoimmune diseases.
{"title":"Engineering red blood cells for antigen-specific immune tolerance and personalized therapy of autoimmune diseases","authors":"Yeshuang Yuan , Mengfan Yu , Xingxing Zhu , Wei Sun , Jing Li , Yiming Wang , Shanbo Yang , Yingying Shi , Zhaolin Wang , Xinyue Wang , Fudi Wang , Yue Xu , Min Wang , Jin Hu , Bo Zhang , Yudong Liu , Xuan Zhang","doi":"10.1016/j.jconrel.2026.114681","DOIUrl":"10.1016/j.jconrel.2026.114681","url":null,"abstract":"<div><div>Current therapies for autoimmune diseases largely rely on broad-spectrum immunosuppressants and biologics, which indiscriminately deplete T or B cells. These approaches are largely constrained by systemic immunosuppression and off-target toxicities. Achieving durable, antigen-specific immune tolerance while preserving protective immunity against pathogens remains a long-standing goal in clinical practice. Here, we present a modular red blood cell (RBC)-based platform that induces antigen-specific tolerance through strain-promoted azide-alkyne cycloaddition (SPAAC)-mediated surface conjugation of disease-relevant peptides. We demonstrated that RBCs engineered by such approach retain their biophysical integrity and biocompatibility across a broad range of conjugation concentrations in vitro. Critically, when conjugated with single or multiple autoantigenic epitopes, these engineered RBCs elicited robust antigen-specific tolerance and drove durable disease remission in two well-established preclinical models, experimental autoimmune encephalomyelitis (EAE) and collagen-induced arthritis (CIA). Further mechanistic investigations revealed that the engineered RBCs reprogram antigen-presenting cells (APCs) toward a tolerogenic phenotype. This reprogramming, in turn, induces anergy in autoreactive T cells and suppresses the activation of autoreactive B cells. Collectively, this work establishes a versatile and clinically translatable platform, offering a path toward personalized, antigen-specific therapy for autoimmune diseases.</div></div>","PeriodicalId":15450,"journal":{"name":"Journal of Controlled Release","volume":"392 ","pages":"Article 114681"},"PeriodicalIF":11.5,"publicationDate":"2026-02-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146134051","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}
Personalized in situ tumor vaccines (ISTVs) have emerged as a promising approach to activating potent T cell-mediated anticancer immunity through the induction of immunogenic cell death (ICD) and the subsequent release of tumor-associated antigens (TAAs). However, their efficacy is limited by non-specific ICD, inadequate TAAs cross-presentation, and the stubborn immunosuppressive tumor microenvironment (TME). Here, we develop a novel ISTV platform (SOM-ZIF-8@Mn/ARV) integrating a specific ICD inducer (ARV-825), and a multifunctional antigen catcher (SOM-ZIF-8@Mn) to boost antitumor immunity. ARV-825, as a protein targeted degradation chimera (PROTAC), selectively degrades bromodomain-containing protein4 (BRD4) to induce potent ICD, while the produced TAAs are effectively captured by SOM-ZIF-8@Mn to in situ generate a vaccination effect. Leveraging its unique hierarchical porous structure and rough surface, SOM-ZIF-8@Mn exhibits enhanced antigen capture efficiency, enabling the adsorption of both soluble TAAs and tumor cell fragments. Additionally, Mn2+ released from SOM-ZIF-8@Mn under TME conditions activates the STING pathway, promotes dendritic cell maturation and antigen cross-presentation, thereby activating CD8+ T cells for efficient tumor-specific immunity. Furthermore, the platform reprograms tumor-associated macrophages into pro-inflammatory M1 phenotypes, alleviating TME immunosuppression. This ISTV platform triggers robust antitumor immunity and achieves significant tumor growth inhibition when combined with αPD-1 blockade. The SOM-ZIF-8@Mn/ARV platform represents a powerful and effective advancement in improving the antitumor immune efficiency of ISTVs, offering a straightforward approach to the challenges faced in tumor immunotherapy.
{"title":"A versatile self-adjuvanting macro-microporous ZIF-8@Mn MOF platform for efficient antigen capture and presentation to boost antitumor immunity","authors":"Qinhua Zuo, Linghong Huang, Yanping Wang, Yifan Cai, Yahui Chen, Chuanxu Zhu, Zonghua Liu, Kewei Wang, Wei Xue","doi":"10.1016/j.jconrel.2026.114707","DOIUrl":"https://doi.org/10.1016/j.jconrel.2026.114707","url":null,"abstract":"Personalized in situ tumor vaccines (ISTVs) have emerged as a promising approach to activating potent T cell-mediated anticancer immunity through the induction of immunogenic cell death (ICD) and the subsequent release of tumor-associated antigens (TAAs). However, their efficacy is limited by non-specific ICD, inadequate TAAs cross-presentation, and the stubborn immunosuppressive tumor microenvironment (TME). Here, we develop a novel ISTV platform (SOM-ZIF-8@Mn/ARV) integrating a specific ICD inducer (ARV-825), and a multifunctional antigen catcher (SOM-ZIF-8@Mn) to boost antitumor immunity. ARV-825, as a protein targeted degradation chimera (PROTAC), selectively degrades bromodomain-containing protein4 (BRD4) to induce potent ICD, while the produced TAAs are effectively captured by SOM-ZIF-8@Mn to in situ generate a vaccination effect. Leveraging its unique hierarchical porous structure and rough surface, SOM-ZIF-8@Mn exhibits enhanced antigen capture efficiency, enabling the adsorption of both soluble TAAs and tumor cell fragments. Additionally, Mn<sup>2+</sup> released from SOM-ZIF-8@Mn under TME conditions activates the STING pathway, promotes dendritic cell maturation and antigen cross-presentation, thereby activating CD8<sup>+</sup> T cells for efficient tumor-specific immunity. Furthermore, the platform reprograms tumor-associated macrophages into pro-inflammatory M1 phenotypes, alleviating TME immunosuppression. This ISTV platform triggers robust antitumor immunity and achieves significant tumor growth inhibition when combined with αPD-1 blockade. The SOM-ZIF-8@Mn/ARV platform represents a powerful and effective advancement in improving the antitumor immune efficiency of ISTVs, offering a straightforward approach to the challenges faced in tumor immunotherapy.","PeriodicalId":15450,"journal":{"name":"Journal of Controlled Release","volume":"110 1","pages":""},"PeriodicalIF":10.8,"publicationDate":"2026-02-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146134052","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}
Bone metastasis is a significant challenge in the treatment of advanced breast cancer, with current treatments mainly providing symptom relief without addressing the osteolytic cycle driven by tumor cells and osteoclasts, which leads to continuous bone destruction and tumor progression. Pamidronate (APD), a nitrogen-containing bisphosphonate, has shown potential in managing osteolytic lesions by inhibiting osteoclast activity. However, its clinical application is hindered by rapid systemic clearance and off-target effects. Herein, we developed a multifunctional injectable hydrogel (CHA) by covalently conjugating APD to enhance localized delivery, reduce toxicity, and target both tumor progression and bone degradation to disrupt osteolytic cycle. The CHA hydrogel induces membrane calcification in tumor cells, forming a mineralized layer that impairs nutrient exchange and suppresses tumor growth. Concurrently, CHA modulates the bone microenvironment by downregulating PTHrP expression, inhibiting osteoclastogenesis, and promoting osteogenesis through the upregulation of OPG and RUNX2. Both in vitro and in vivo experiments demonstrated that CHA significantly inhibited tumor growth, prevented bone loss, and facilitated bone regeneration. Moreover, CHA exhibited excellent biocompatibility with no observed systemic toxicity. These results underscore the promise of CHA as a clinically translatable therapeutic strategy for the treatment of osteolytic bone metastases.
{"title":"Injectable hydrogel induces tumor cell extracellular calcification and bone regeneration to disrupt the osteolytic vicious cycle in bone metastasis","authors":"Minzhao Lin, Shaohui Deng, Simin Liang, Yujie Jiang, Qi Chen, Gengjia Chen, Bo Li, Yujun Cai, Xiaoxue Xie, Xintao Shuai, Zecong Xiao","doi":"10.1016/j.jconrel.2026.114701","DOIUrl":"https://doi.org/10.1016/j.jconrel.2026.114701","url":null,"abstract":"Bone metastasis is a significant challenge in the treatment of advanced breast cancer, with current treatments mainly providing symptom relief without addressing the osteolytic cycle driven by tumor cells and osteoclasts, which leads to continuous bone destruction and tumor progression. Pamidronate (APD), a nitrogen-containing bisphosphonate, has shown potential in managing osteolytic lesions by inhibiting osteoclast activity. However, its clinical application is hindered by rapid systemic clearance and off-target effects. Herein, we developed a multifunctional injectable hydrogel (CHA) by covalently conjugating APD to enhance localized delivery, reduce toxicity, and target both tumor progression and bone degradation to disrupt osteolytic cycle. The CHA hydrogel induces membrane calcification in tumor cells, forming a mineralized layer that impairs nutrient exchange and suppresses tumor growth. Concurrently, CHA modulates the bone microenvironment by downregulating PTHrP expression, inhibiting osteoclastogenesis, and promoting osteogenesis through the upregulation of OPG and RUNX2. Both <em>in vitro</em> and <em>in vivo</em> experiments demonstrated that CHA significantly inhibited tumor growth, prevented bone loss, and facilitated bone regeneration. Moreover, CHA exhibited excellent biocompatibility with no observed systemic toxicity. These results underscore the promise of CHA as a clinically translatable therapeutic strategy for the treatment of osteolytic bone metastases.","PeriodicalId":15450,"journal":{"name":"Journal of Controlled Release","volume":"3 1","pages":""},"PeriodicalIF":10.8,"publicationDate":"2026-02-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146134057","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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