Journal of Controlled Release最新文献

{"title":"Engineering whole tumor cell vaccines for cancer immunotherapy: From malignant cells to therapeutic vaccines.","authors":"Chuhan Wu, Zongyu Xia, Linxi Huang, Jingsheng Huang, Wei Zhu, Yun Chen","doi":"10.1016/j.jconrel.2026.115465","DOIUrl":"https://doi.org/10.1016/j.jconrel.2026.115465","url":null,"abstract":"<p><p>Tumor cells are the driving force of cancer progression, yet they also constitute a rich reservoir of tumor-associated and patient-specific antigens that can be harnessed for therapeutic vaccination. Whole tumor cell vaccines (WTCVs) exploit this unique duality by converting malignant cells into immunotherapeutic agents capable of eliciting broad antitumor immunity and overcoming tumor heterogeneity. However, their clinical translation remains constrained by the need to eliminate tumorigenic potential while preserving or enhancing immunogenicity. Here, we provide a comprehensive overview of recent advances in the engineering of WTCVs from the perspectives of safety assurance and therapeutic enhancement. We summarize current strategies for controlling tumorigenicity, including physical, chemical, engineered, and viability-preserving approaches, and discuss emerging immunopotentiation strategies that enhance antigen abundance and exposure, improve antigen presentation, activate innate and adaptive immune pathways, and integrate complementary therapeutic modalities. Collectively, these advances are transforming malignant cells into multifunctional therapeutic vaccines capable of eliciting potent and durable antitumor immunity. Finally, we discuss the key challenges and future opportunities for next-generation WTCVs and highlight design principles that may accelerate their clinical translation.</p>","PeriodicalId":15450,"journal":{"name":"Journal of Controlled Release","volume":" ","pages":"115465"},"PeriodicalIF":12.4,"publicationDate":"2026-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149227993","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mechanistic benchmarking of SNAC, DDM, and LLC reveals enhancer-dependent pathways for intestinal semaglutide delivery.","authors":"Banghao Yuan, Yusheng Sui, Hanxiang Li, Jinyan Huang, Ye Chan Oh, Yajie Zhao, Xueyu Li, Yuheng Sun, Liu Dou, Abdul W Basit, Yang Mai","doi":"10.1016/j.jconrel.2026.115455","DOIUrl":"https://doi.org/10.1016/j.jconrel.2026.115455","url":null,"abstract":"<p><p>The oral delivery of peptide therapeutics remains constrained by poor intestinal permeability and the challenge of enhancing epithelial transport without compromising mucosal integrity. Although sodium N-(8-[2-hydroxybenzoyl]amino) caprylate (SNAC) enables gastric absorption of oral semaglutide and has also been explored for small-intestinal absorption of other peptide drugs, its suitability for enteric intestinal delivery of semaglutide remains unexplored. Here, we performed a comparative mechanistic evaluation of three permeation enhancers (SNAC, N-dodecyl-β-D-maltoside, and lauroyl-l-carnitine) for enteric delivery of semaglutide. Mechanisms were screened in epithelial monolayers and in situ intestinal absorption in rats, and the enhancers carried forward were formulated into enteric-coated capsules and evaluated in beagle dogs, with the leading candidate taken in to cynomolgus monkeys. In differentiated Caco-2 monolayers, all enhancers increased semaglutide transport but exhibited distinct transport mechanisms and barrier-response profiles. SNAC increased permeability without increasing mannitol transport or disrupting ZO-1, indicating a largely non-paracellular, cargo-dependent profile. DDM markedly increased paracellular marker transport and disrupted tight-junction organization, consistent with a primarily paracellular mode of action associated with reduced barrier recoverability. LLC showed a more favorable balance between transport enhancement and barrier recovery, while also increasing intracellular semaglutide-associated fluorescence and FD4 permeability. Rab5 immunostaining and dynasore inhibition indicated a dynamin-sensitive uptake component alongside partial tight-junction modulation. In rats, LLC produced the greatest increase in semaglutide absorption, and this effect was substantially attenuated by dynasore co-treatment. Transmission electron microscopy and tissue immunofluorescence further supported the presence of LLC-associated micelle-like structures, Rab5-related intracellular trafficking and junctional remodelling, with no overt tissue injury on local or systemic histology. For large-animal translation, citric acid and L-arginine improved semaglutide stability in intestinal fluids, and the resulting LLC-containing enteric formulation markedly increased systemic exposure in orally dosed beagle dogs and in cynomolgus monkeys following intraduodenal delivery. Collectively, these findings identify LLC as a promising permeation enhancer within the present SNAC/DDM/LLC comparison for enteric intestinal delivery of semaglutide and highlight how coordinated uptake-related and barrier-modulating mechanisms can support intestinal semaglutide absorption.</p>","PeriodicalId":15450,"journal":{"name":"Journal of Controlled Release","volume":" ","pages":"115455"},"PeriodicalIF":12.4,"publicationDate":"2026-10-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149224144","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Annexin A5-engineered nanovaccines synchronize spatiotemporal antigen release with phagocytosis checkpoint blockade for potent in situ cancer immunotherapy.","authors":"Tianjiao Wang, Lu Wang, Xiaoying Kang, Junyan Jiang, Baohui Yuan, Lu Zhang, Xuya Yu, Ting Chen, Xueping Li, Yuan Zhang, Wen Meng, Jian Li, Ji Qi, Dan Ding, Yang Shi, Wen Li","doi":"10.1016/j.jconrel.2026.115460","DOIUrl":"https://doi.org/10.1016/j.jconrel.2026.115460","url":null,"abstract":"<p><p>In situ generation of autologous tumor vaccines from dying tumor cells offers a promising route for personalized cancer immunotherapy, yet is often limited by phosphatidylserine (PS)-mediated immunosuppressive clearance that can restrict downstream immune activation and favor M2-like macrophage polarization. Here, we report a sequentially orchestrated nanovaccine (NT@ANX5-P) that couples photodynamic therapy (PDT)-induced immunogenic tumor-cell damage with on-demand PS masking to enhance in situ tumor vaccination. The nanovaccine consists of a photosensitizer core cloaked with genetically engineered tumor cell membranes displaying Annexin A5 (ANX5) and further shielded by a ROS-cleavable PEG layer for circulatory shielding and local light-responsive activation. Upon localized light irradiation, tumor cells undergo PDT-induced damage and apoptosis, while ROS-triggered PEG cleavage increases ANX5 accessibility for binding exposed PS, thereby attenuating PS-dependent efferocytic clearance and favoring progression toward secondary necrosis. This coordinated treatment enhanced dendritic cell maturation, remodeled tumor-associated macrophage phenotypes, and increased T-cell responses. In 4T1 tumor-bearing mice, NT@ANX5-P suppressed primary and distant tumor growth, reduced lung metastasis, and induced protection against homologous tumor rechallenge. CD8⁺ T-cell depletion markedly weakened bilateral tumor control, supporting an important functional contribution of CD8⁺ T cells. These findings provide proof-of-concept for coordinating PDT-induced antigen generation with spatially regulated modulation of PS-dependent dying-cell clearance in the 4T1 model.</p>","PeriodicalId":15450,"journal":{"name":"Journal of Controlled Release","volume":" ","pages":"115460"},"PeriodicalIF":12.4,"publicationDate":"2026-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149207092","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mitochondria-targeted drug delivery systems for aging-related diseases: Mechanisms, strategies, and advances.","authors":"Fang Zhang, Haotian Ma, Siyu Zhou, Shasha Ran, Maiheliya Abulajiang, Shanshan Li, Qixiong Zhang","doi":"10.1016/j.jconrel.2026.115463","DOIUrl":"https://doi.org/10.1016/j.jconrel.2026.115463","url":null,"abstract":"<p><p>Mitochondrial dysfunction, characterized by increased oxidative stress, impaired energy metabolism, disrupted mitochondrial dynamics, abnormal quality control, and activation of apoptosis, represents a critical pathological basis for a wide range of aging-related diseases (ARDs), including neurodegenerative diseases, cardiovascular disorders, sarcopenia, and osteoarthritis. Mitochondria-targeted drug delivery systems increase the effective concentration of bioactive molecules within these dysfunctional organelles, offering novel strategies for the precise modulation of mitochondrial function. This review summarizes structural and functional changes in mitochondria during aging and their associations with major ARDs. We comprehensively review key advances in the design principles, mechanisms of action, and applications of passive targeting, stimuli-responsive systems, active targeting, and biomimetic drug delivery platforms. In addition, emerging interventions such as NAD⁺ supplementation, mitochondrial gene delivery, EV-mediated mitochondrial delivery and mitochondrial transplantation are discussed. Despite the demonstrated potential of these systems to restore mitochondrial homeostasis and tissue functionality in various disease models, their clinical translation remains constrained by obstacles including unstable targeting efficacy under pathological conditions, insufficient long-term safety of materials, manufacturing complexity, and a lack of standardized evaluation criteria. Future efforts should focus on integrating disease heterogeneity, advanced materials, and multi-omics technologies to advance mitochondria-targeted therapies toward standardization, individualization, and diagnostic-therapeutic integration.</p>","PeriodicalId":15450,"journal":{"name":"Journal of Controlled Release","volume":" ","pages":"115463"},"PeriodicalIF":12.4,"publicationDate":"2026-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149207220","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Advancing biopharmaceutics modelling of extended-release formulations with sequential TIM-1/TIM-2 biorelevant upper GI and colonic dissolution.","authors":"Connor O'Farrell, Maitrayee Chatterjee, Lieke W J van den Elsen, Tânia Martins Garcia, Dan Barnhill","doi":"10.1016/j.jconrel.2026.115461","DOIUrl":"https://doi.org/10.1016/j.jconrel.2026.115461","url":null,"abstract":"<p><p>Predicting the in vivo performance of extended-release (ER) products is difficult because drug release is excipient-controlled and may continue into the colon, a region poorly represented by conventional dissolution methods. Here, during ER formulation development, a biorelevant in vitro-in silico workflow was established to support formulation development of rocavorexant, a weakly water-soluble, high-permeability BCS II compound formulated as a HPMC-matrix ER tablet. Formulations were screened for food effect risk using the dynamic in vitro TIM-1 gastrointestinal model, before dissolution profiles measured in sequential TIM-1/TIM-2 upper-GI and colonic transit were used as dissolution input for PBBM. TIM-derived dissolution profiles were constructed from luminal samples, distinguishing apparently dissolved from dispersed drug, and from filtrate/dialysate fractions from the jejunal, ileal and colonic compartments representing dissolved drug removed from the systems. PBBM using conventional USP-I dissolution, either directly or after level A IVIVC transformation, failed to reproduce clinical pharmacokinetics, underpredicting early exposure and missing a late 20-24 h plasma plateau. Sequential TIM-1/TIM-2 input predicted clinical exposure well (predicted/observed C_max 1.03; AUC 0.91-0.94), recovered the plateau and linked regional release, solubilisation, absorption and systemic pharmacokinetics.</p>","PeriodicalId":15450,"journal":{"name":"Journal of Controlled Release","volume":" ","pages":"115461"},"PeriodicalIF":12.4,"publicationDate":"2026-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149207089","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A dual-gated engineered bacterial platform for spatiotemporally controlled precise protein degradation.","authors":"Shangwu Sun, Ruoxi Hu, Xue Zhai, Rui Bai, Jiaming Guo, Tuoyu Zhou, Tongfu Yang, Qinglan Zeng, Yilin Zhang, Jie Yu, Renke Li, Zuguang Wu, Zhaoting Li","doi":"10.1016/j.jconrel.2026.115459","DOIUrl":"https://doi.org/10.1016/j.jconrel.2026.115459","url":null,"abstract":"<p><p>Lysosome-targeting chimeras (LYTACs) have attracted much attention due to their ability to specifically target and degrade disease-related proteins on the cell membrane. However, their clinical application is limited by poor tumor specificity, systemic off-target effects, and a lack of temporal regulation. Engineered bacteria naturally home to tumors and serve as in situ production factories, but current approaches typically lack orthogonal regulation over payload release and functional activation, leading to premature exposure and suboptimal efficacy. Here, we develop a dual-gated engineered bacterial platform (DGTPB) that decouples LYTAC delivery from functional activation. Upon tumor colonization, DGTPB constitutively produces genetically encoded LYTACs, triggers their release via L-arabinose-induced bacterial lysis, and subsequently activates targeted degradation through red-light irradiation. This dual-gating design ensures high local LYTAC concentrations while minimizing systemic exposure. We demonstrate that DGTPB-mediated degradation of EGFR and PD-L1 potently suppresses tumor growth and metastasis in both melanoma and breast cancer models. Owing to its modular architecture, DGTPB is readily reprogrammable against diverse disease-associated membrane proteins by simply exchanging targeting ligands. Collectively, DGTPB establishes a versatile, programmable, and safe framework for precision extracellular targeted protein degradation, thereby providing a new tool for engineered-bacteria-based platforms in cancer immunotherapy.</p>","PeriodicalId":15450,"journal":{"name":"Journal of Controlled Release","volume":" ","pages":"115459"},"PeriodicalIF":12.4,"publicationDate":"2026-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149207109","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Nanomedicine strategies for overcoming cellular and microenvironmental barriers to cuproptosis-based cancer therapy.","authors":"Lei Ge, Dong Wang, Ben Zhong Tang","doi":"10.1016/j.jconrel.2026.115462","DOIUrl":"https://doi.org/10.1016/j.jconrel.2026.115462","url":null,"abstract":"<p><p>Cuproptosis, a copper-dependent form of regulated cell death driven by mitochondrial proteotoxic stress, has emerged as a promising vulnerability for cancer therapy. However, its therapeutic translation is limited by cellular and microenvironmental barriers that restrict effective copper delivery, intracellular copper accumulation, mitochondrial engagement, and antitumor immune activation. This review summarizes the molecular basis of cuproptosis, including copper homeostasis, mitochondrial copper trafficking, lipoylated protein aggregation, and iron‑sulfur cluster disruption. We then examine how dysregulated copper transport, glutathione-mediated buffering, metabolic reprogramming, hypoxia, and immunosuppressive tumor microenvironments attenuate cuproptosis-based treatment. Focusing on these barriers, we discuss nanomedicine strategies designed to modulate copper homeostasis, deplete glutathione, reprogram tumor metabolism, alleviate hypoxia, and enhance antitumor immunity. These multifunctional platforms can enable tumor-selective copper delivery and spatiotemporally controlled activation while integrating complementary therapeutic modalities. Finally, we highlight unresolved challenges, including incomplete mechanistic understanding, tumor heterogeneity, insufficient real-time monitoring of cuproptosis, and the need to balance therapeutic efficacy with systemic copper toxicity. A systems-level integration of nanomedicine, mechanistic biology, and computational design may support the development of safer, more precise, and clinically actionable cuproptosis-based cancer therapies.</p>","PeriodicalId":15450,"journal":{"name":"Journal of Controlled Release","volume":" ","pages":"115462"},"PeriodicalIF":12.4,"publicationDate":"2026-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149207177","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Decoding extracellular vesicle-biomolecule interactions: How the biomolecular corona shapes extracellular vesicle biodistribution and clearance in vivo.","authors":"Xiaoyan Fang, Tianchang He, Hao Fan, Xiaofei Li, Luying Zhou, Wenhua Yang, Lina Zhu, Yuting Ge, Wenshuai Han, Yu Gao, Volker Mailänder, Daniel Crespy, Katharina Landfester, Junfeng Zhang, Shuai Jiang","doi":"10.1016/j.jconrel.2026.115447","DOIUrl":"https://doi.org/10.1016/j.jconrel.2026.115447","url":null,"abstract":"<p><p>Extracellular vesicles (EVs) are promising endogenous nanocarriers, yet how biomolecules adsorption shapes their in vivo fate remains unclear. Here, we examine how biomolecular corona formation regulates the biodistribution, cellular recognition, and clearance of extracellular vesicles. Using EVs derived from macrophages and breast cancer cells, together with artificially prepared cell membrane-derived vesicles (CVs) generated from the corresponding parental cells as controls, we observed markedly different circulation and clearance behaviors despite their comparable physicochemical properties. Proteomic analyses revealed distinct and extensive biomolecular adsorption profiles on EVs compared with their corresponding CVs. In vivo imaging shows that EVs undergo faster systemic clearance and preferential accumulation in the liver and spleen. Cellular-level analyses identify Kupffer cells, liver sinusoidal endothelial cells, splenic macrophages, and circulating innate immune cells-especially neutrophils-as key mediators of EVs clearance. In vitro studies further confirm that biomolecular corona formation enhances immune recognition and uptake, with EVs consistently showing higher phagocytosis than CVs. Notably, opsonin proteins such as complement C3 and immunoglobulins are enriched on EVs surfaces and strongly correlate with increased macrophage uptake. Overall, these results highlight biomolecular corona formation as a critical determinant of EVs biological identity and in vivo fate.</p>","PeriodicalId":15450,"journal":{"name":"Journal of Controlled Release","volume":" ","pages":"115447"},"PeriodicalIF":12.4,"publicationDate":"2026-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149207217","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Hierarchically sequential targeting nanoplatform suppresses NETosis-promoted angiogenesis for corneal neovascularization therapy.","authors":"Chaoqun Wei, Xiaoxue Liu, Yingxuan Bi, Longfei Zhao, Jiahao Shi, Yifei Li, Kejuan Jia, Changlong Wang, Hua Gao","doi":"10.1016/j.jconrel.2026.115458","DOIUrl":"https://doi.org/10.1016/j.jconrel.2026.115458","url":null,"abstract":"<p><p>Corneal neovascularization (CorNV) lacks effective therapies due to poor drug delivery and a complex inflammatory microenvironment, necessitating a deeper understanding of the underlying pathogenic mechanisms and the development of efficient delivery systems. Here we show that neutrophil extracellular traps (NETs) are pathologically activated in CorNV and identify peptidyl arginine deiminase 4 (PAD4) as a key therapeutic target. To achieve coordinated inhibition of NETosis and downstream vascular endothelial growth factor (VEGF) signaling, we engineer a reactive oxygen species (ROS) responsive copolymer encapsulating the PAD4 inhibitor Cl-amidine (Ca@PNH) that hierarchically targets neovascular endothelial cells and activated neutrophils via HRH and neutrophil elastase binding peptide (NEBP) peptides. Upon topical administration, Ca@PNH achieves prolonged ocular retention and lesion specific ROS triggered drug release, suppressing both NETs formation and angiogenesis. In a mouse CorNV model, this spatiotemporal strategy effectively treats neovascularization with excellent safety. Collectively, our work systematically establishes NETs as critical drivers of CorNV, identifies PAD4 as a druggable target, and offers a hierarchical delivery paradigm for inflammation driven ocular diseases.</p>","PeriodicalId":15450,"journal":{"name":"Journal of Controlled Release","volume":" ","pages":"115458"},"PeriodicalIF":12.4,"publicationDate":"2026-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149193888","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Phenylboronate hydrogel for administration route tailored dual-drug delivery to anterior and posterior ocular segments.","authors":"Rui Xue Zhang, Xu Wang, Xu Yan, Wei Jia Yan, Xue-Ting Wang, Yan Chen, Xudong Deng, Weijia Lu, Yexuan Guo, Hong Yan","doi":"10.1016/j.jconrel.2026.115448","DOIUrl":"https://doi.org/10.1016/j.jconrel.2026.115448","url":null,"abstract":"<p><p>Frequent multidrug eyedrop instillation for ocular perioperative prophylaxis (e.g., cataract surgery) suffers from rapid nasolacrimal clearance, limited corneal penetration, and poor access to the posterior segment. To address these limitations, we engineered an interface-adaptive phenylboronate ester hydrogel for rapid in situ gelation and the co-entrapment of two frequently instilled drugs (moxifloxacin and dexamethasone) in their free or liposomal forms at physiological pH. This platform utilizes chemical crosslinking between hyaluronic acid-conjugated 2-aminophenylboronic acid and the diols of polyvinyl alcohol (HA-2APBA@PVA), forming a dynamic hydrogel network via phenylboronate ester bonds with a thermodynamically favorable formation energy (ΔG = -10.64 kcal/mol). This unique chemistry imparts shear-thinning injectability through fine ophthalmic needles, ensures mechanical stability against blink-induced shearing, and drives robust mucoadhesion with tear film mucins such as MUC5AC for prolonged ocular retention at the injection site. Architecturally, a \"liposome-in-gel\" system establishes hierarchical diffusion steps that suppress the initial burst effect and extend drug release duration by >2-fold compared to the free-drug solution control. The hydrogel demonstrates excellent ophthalmic compatibility, exhibiting physiological osmolality, >80% optical transmittance, and near 100% viability in human corneal and retinal pigment epithelial cells. Safety was further validated via Draize irritation testing and preserved ocular histology across topical and periocular administration routes. Unlike the rapid washout of standard eyedrops, this hydrogel depot ensures prolonged ocular surface retention. Pharmacokinetic analysis revealed route-dependent versatility: compared to standard eyedrops, subconjunctival administration enhanced anterior segment exposure of moxifloxacin and dexamethasone by 14.9- and 8.6-fold, respectively, while sub-Tenon dosing facilitated targeted delivery to the posterior segment. This single, dynamic covalent chemistry provides a scalable, clinically compatible alternative strategy to eyedrops and advances multidrug therapies across both ocular segments.</p>","PeriodicalId":15450,"journal":{"name":"Journal of Controlled Release","volume":" ","pages":"115448"},"PeriodicalIF":12.4,"publicationDate":"2026-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149182154","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}