Lipid nanoparticles (LNPs) have demonstrated great potential in drug delivery. To fully unlock the therapeutic effect for various diseases, specific design and optimization of the LNP are necessary, which entails an efficient workflow to navigate the LNP design space and tailor the critical attributes. The convergence of high-throughput technology and artificial intelligence (AI) may provide a transformative paradigm to address this challenge. While high-throughput technology serves as a crucial strategy to generate the reliable, large-scale datasets, AI can correlate the critical biological attributes with the LNP structures by learning from the experimental data obtained through the high-throughput method, enabling efficient LNP discovery. In this review, we will discuss the establishment of datasets through high-throughput technology for AI training. AI-assisted LNP design and optimization will be then summarized. Finally, we give an outlook and challenge to discuss the applications of AI for future clinical LNP development.
{"title":"High-throughput, AI-assisted design and optimization of lipid nanoparticles for drug delivery","authors":"Junjie Zeng, Runlin Chen, Shun He, Chong Zhang, Wen-Che Liu, Hao Song, Shuai Liu, Kewang Nan","doi":"10.1016/j.jconrel.2025.114573","DOIUrl":"https://doi.org/10.1016/j.jconrel.2025.114573","url":null,"abstract":"Lipid nanoparticles (LNPs) have demonstrated great potential in drug delivery. To fully unlock the therapeutic effect for various diseases, specific design and optimization of the LNP are necessary, which entails an efficient workflow to navigate the LNP design space and tailor the critical attributes. The convergence of high-throughput technology and artificial intelligence (AI) may provide a transformative paradigm to address this challenge. While high-throughput technology serves as a crucial strategy to generate the reliable, large-scale datasets, AI can correlate the critical biological attributes with the LNP structures by learning from the experimental data obtained through the high-throughput method, enabling efficient LNP discovery. In this review, we will discuss the establishment of datasets through high-throughput technology for AI training. AI-assisted LNP design and optimization will be then summarized. Finally, we give an outlook and challenge to discuss the applications of AI for future clinical LNP development.","PeriodicalId":15450,"journal":{"name":"Journal of Controlled Release","volume":"29 1","pages":""},"PeriodicalIF":10.8,"publicationDate":"2025-12-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145813844","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 : 2025-12-22DOI: 10.1016/j.jconrel.2025.114572
Yichen Liu, Gaeun Kim, Runyao Zhu, Hyunsu Jeon, Yichun Wang
Tumor hypoxia and poor penetration of therapeutics across tumor-microenvironment barriers remain major obstacles to effective cancer therapy, including photodynamic therapy (PDT). Here we introduce a nanochirality-programmed assembly (L-Chi-GAIN) in which nanochirality drives site-selective assembly that activates Type-I reactive oxygen species (ROS) generation with significantly reduced oxygen dependence and diminishes hyaluronan-mediated matrix adhesion, thereby enabling deep intratumoral therapy. Glycosylation imparts structural chirality to graphene quantum dots (GQDs), directing site-selective assembly of indocyanine green (ICG) that turns on photoinduced electron transfer (PET), producing a 64-fold increase in ROS relative to free ICG. Nanochirality also modulates assembly–extracellular matrix (ECM) interactions. L-GQDs show a less favorable hyaluronan binding free energy (ΔGbind), thereby accelerating interstitial transport and resulting in ∼3-fold greater penetration depth and ∼ 21-fold higher mean intratumoral ICG signal within the penetrating area relative to liposomal carriers. Under near-infrared irradiation, L-Chi-GAIN elicits strong oxidative stress and triggers Gasdermin-D (GSDMD)-dependent pyroptosis, leading to significant suppression of tumor growth. This work offers a nanochirality-guided design strategy for PDT in deep tumors by coupling site-selective assembly with stereoselective navigation of the ECM.
{"title":"Nanochirality-programmed type-I photosensitizer enables deep-tumor photodynamic therapy by reducing extracellular-matrix adhesion","authors":"Yichen Liu, Gaeun Kim, Runyao Zhu, Hyunsu Jeon, Yichun Wang","doi":"10.1016/j.jconrel.2025.114572","DOIUrl":"10.1016/j.jconrel.2025.114572","url":null,"abstract":"<div><div>Tumor hypoxia and poor penetration of therapeutics across tumor-microenvironment barriers remain major obstacles to effective cancer therapy, including photodynamic therapy (PDT). Here we introduce a nanochirality-programmed assembly (<em>L</em>-Chi-GAIN) in which nanochirality drives site-selective assembly that activates Type-I reactive oxygen species (ROS) generation with significantly reduced oxygen dependence and diminishes hyaluronan-mediated matrix adhesion, thereby enabling deep intratumoral therapy. Glycosylation imparts structural chirality to graphene quantum dots (GQDs), directing site-selective assembly of indocyanine green (ICG) that turns on photoinduced electron transfer (PET), producing a 64-fold increase in ROS relative to free ICG. Nanochirality also modulates assembly–extracellular matrix (ECM) interactions. <em>L</em>-GQDs show a less favorable hyaluronan binding free energy (ΔG<sub>bind</sub>), thereby accelerating interstitial transport and resulting in ∼3-fold greater penetration depth and ∼ 21-fold higher mean intratumoral ICG signal within the penetrating area relative to liposomal carriers. Under near-infrared irradiation, <em>L</em>-Chi-GAIN elicits strong oxidative stress and triggers Gasdermin-D (GSDMD)-dependent pyroptosis, leading to significant suppression of tumor growth. This work offers a nanochirality-guided design strategy for PDT in deep tumors by coupling site-selective assembly with stereoselective navigation of the ECM.</div></div>","PeriodicalId":15450,"journal":{"name":"Journal of Controlled Release","volume":"390 ","pages":"Article 114572"},"PeriodicalIF":11.5,"publicationDate":"2025-12-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145812893","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 : 2025-12-22DOI: 10.1016/j.jconrel.2025.114569
Chenchen Zhang , Yuerong Bai , Qimeng Yin , Jiahao Li , Kun Huang , Min Qiu
Liver fibrosis is a major global health burden with no approved therapies. Transient expression of reprogramming factors Oct4, Sox2, and Klf4 (OSK) promotes tissue regeneration without inducing full pluripotency, which represents an attractive regenerative therapy. Here, we introduce a hepatocyte-specific mRNA delivery strategy for in vivo partial cellular reprogramming using a chemically defined lipid nanoparticle (LNP) platform. We synthesized a series of natural unsaturated fatty alcohol-based ionizable lipids and identified a lead compound, H4T3, with mRNA delivery efficacy comparable to SM102. Further formulation optimization led to a simplified, phospholipid-free, three-component LNP formulation, H4T3_F6 that exhibits high potency and enhanced hepatocyte selectivity, alongside minimal immunogenicity and an overall favorable safety profile. Hepatocyte-specific delivery of OSK mRNA via H4T3_F6 LNPs transiently reprogrammed fibrotic hepatocytes into progenitor-like cells, rejuvenated hepatic gene expression, and promoted functional regeneration. This rejuvenation process downregulates fibrogenic mediators (Tgfb1, Pdgfb), disrupting hepatocyte-stellate cell signaling and halting extracellular matrix (ECM) deposition. The integrated reprogramming and paracrine modulation collectively shift the liver microenvironment from a fibrotic to a regenerative state in a CCl4-induced liver fibrosis mouse model. This study provides proof-of-concept for rejuvenating fibrotic livers via selective mRNA-based in vivo cellular reprogramming, offering a promising strategy for liver fibrosis or age-related tissue repair.
{"title":"Hepatocyte-specific partial cellular reprogramming via selective OSK mRNA lipid nanoparticle attenuates liver fibrosis","authors":"Chenchen Zhang , Yuerong Bai , Qimeng Yin , Jiahao Li , Kun Huang , Min Qiu","doi":"10.1016/j.jconrel.2025.114569","DOIUrl":"10.1016/j.jconrel.2025.114569","url":null,"abstract":"<div><div>Liver fibrosis is a major global health burden with no approved therapies. Transient expression of reprogramming factors <em>Oct4</em>, <em>Sox2,</em> and <em>Klf4</em> (<em>OSK</em>) promotes tissue regeneration without inducing full pluripotency, which represents an attractive regenerative therapy. Here, we introduce a hepatocyte-specific mRNA delivery strategy for <em>in vivo</em> partial cellular reprogramming using a chemically defined lipid nanoparticle (LNP) platform. We synthesized a series of natural unsaturated fatty alcohol-based ionizable lipids and identified a lead compound, H4T3, with mRNA delivery efficacy comparable to SM102. Further formulation optimization led to a simplified, phospholipid-free, three-component LNP formulation, H4T3_F6 that exhibits high potency and enhanced hepatocyte selectivity, alongside minimal immunogenicity and an overall favorable safety profile. Hepatocyte-specific delivery of <em>OSK</em> mRNA <em>via</em> H4T3_F6 LNPs transiently reprogrammed fibrotic hepatocytes into progenitor-like cells, rejuvenated hepatic gene expression, and promoted functional regeneration. This rejuvenation process downregulates fibrogenic mediators (<em>Tgfb1</em>, <em>Pdgfb</em>), disrupting hepatocyte-stellate cell signaling and halting extracellular matrix (ECM) deposition. The integrated reprogramming and paracrine modulation collectively shift the liver microenvironment from a fibrotic to a regenerative state in a CCl<sub>4</sub>-induced liver fibrosis mouse model. This study provides proof-of-concept for rejuvenating fibrotic livers <em>via</em> selective mRNA-based <em>in vivo</em> cellular reprogramming, offering a promising strategy for liver fibrosis or age-related tissue repair.</div></div>","PeriodicalId":15450,"journal":{"name":"Journal of Controlled Release","volume":"390 ","pages":"Article 114569"},"PeriodicalIF":11.5,"publicationDate":"2025-12-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145813845","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 : 2025-12-22DOI: 10.1016/j.jconrel.2025.114565
Xiang-Yun Du, Yin-Jian Song, Chen Du, Ji-Dong Liu
Delayed skin wound healing caused by bacterial infection and persistent oxidative stress has been considered as a frequently encountered clinical problem that significantly affects patients' health. However, the real-time monitoring and on-demand treatment of non-healing wounds remain a great challenge. Herein, a feasible strategy is developed to core-shell polymer/hydrogel microfibers by integrating microfluidic spinning with shear-flow-induced coating technology. The fabricated self-healing microfibers are facilely assembled into nonwoven fabrics through reversible physical interactions. The core polycaprolactone (PCL) acting as a skeleton endows fabrics with structural and mechanical robustness (4.67 MPa), while the hydrogel shell brings functional diversity including great flexibility, self-healing, self-adhesion and pH-responsive swelling capability. By introducing epigallocatechin gallate (EGCG) in core PCL phase, the remarkable reactive oxygen species (ROS) cleaning capacity (93.8 % for 0.5 h) and antibacterial activity against E. coli (98.7 %) and S. aureus (99.6 %) are achieved. Particularly, the pH-regulated drug release of fabric in a prolonged form is achieved owing to the reversibly swelling/shrinking behavior of hydrogel shell with the changed environmental pH, which is expected to realize on-demand drug delivery and treatment of wound. Additionally, the pH-responsive curcumin-loaded mesoporous microparticles are incorporated into hydrogel shell, aiming to visually real-time detect pH level in a high-efficiency and reversible manner. Moreover, the fabric can serve as a flexible wearable sensor for precisely monitoring motions of patients. This strategy explores a feasible solution to diligently tracking wound pH and movements, along with inhibiting wound infection, substantiating a great foundation for application in personalized, intelligent and precise theranostic wound dressings.
{"title":"Multifunctional microfluidic-directed polymer/hydrogel fabrics towards pH-responsive drug delivery, wound monitoring and wearable sensing","authors":"Xiang-Yun Du, Yin-Jian Song, Chen Du, Ji-Dong Liu","doi":"10.1016/j.jconrel.2025.114565","DOIUrl":"10.1016/j.jconrel.2025.114565","url":null,"abstract":"<div><div>Delayed skin wound healing caused by bacterial infection and persistent oxidative stress has been considered as a frequently encountered clinical problem that significantly affects patients' health. However, the real-time monitoring and on-demand treatment of non-healing wounds remain a great challenge. Herein, a feasible strategy is developed to core-shell polymer/hydrogel microfibers by integrating microfluidic spinning with shear-flow-induced coating technology. The fabricated self-healing microfibers are facilely assembled into nonwoven fabrics through reversible physical interactions. The core polycaprolactone (PCL) acting as a skeleton endows fabrics with structural and mechanical robustness (4.67 MPa), while the hydrogel shell brings functional diversity including great flexibility, self-healing, self-adhesion and pH-responsive swelling capability. By introducing epigallocatechin gallate (EGCG) in core PCL phase, the remarkable reactive oxygen species (ROS) cleaning capacity (93.8 % for 0.5 h) and antibacterial activity against <em>E. coli</em> (98.7 %) and <em>S. aureus</em> (99.6 %) are achieved. Particularly, the pH-regulated drug release of fabric in a prolonged form is achieved owing to the reversibly swelling/shrinking behavior of hydrogel shell with the changed environmental pH, which is expected to realize on-demand drug delivery and treatment of wound. Additionally, the pH-responsive curcumin-loaded mesoporous microparticles are incorporated into hydrogel shell, aiming to visually real-time detect pH level in a high-efficiency and reversible manner. Moreover, the fabric can serve as a flexible wearable sensor for precisely monitoring motions of patients. This strategy explores a feasible solution to diligently tracking wound pH and movements, along with inhibiting wound infection, substantiating a great foundation for application in personalized, intelligent and precise theranostic wound dressings.</div></div>","PeriodicalId":15450,"journal":{"name":"Journal of Controlled Release","volume":"390 ","pages":"Article 114565"},"PeriodicalIF":11.5,"publicationDate":"2025-12-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145801408","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 : 2025-12-22DOI: 10.1016/j.jconrel.2025.114571
Deqi Cai , Chong Su , Mingyang Zhao , Huan Yang , Zhe Zhang , Yingze Liu , Jingkai Gu
DSPE-PEG2000 (1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-poly(ethylene glycol)-2000), a key excipient of stealth nano-formulations like Doxil®, prolongs nano-carrier blood residence by forming steric hydrophilic barriers. However, its assumed biological inertness faces challenges from emerging PEG-related risks. Limited by analytical methods, its in vivo fate and biomacromolecular interactions remain uncharacterized. Here, Liquid Chromatography-Quadrupole/Time-of-Flight Mass Spectrometry (LC-Q-TOF MS) and anti-PEG single-chain variable fragment (PEG-scFv) strategy were innovatively employed to decode DSPE-PEG2000's biological properties post-intravenous administration. Results reveal a short plasma half-life, tissue-specific distribution in lung, liver, and spleen, complement activation without adaptive antibody response, cleavage to DSPE/PEG2000 with renal excretion/degradation of PEG2000, and a plasma protein binding rate (PPB) of 63.2 ± 7.11 % that competitively displaces 50 % of doxorubicin binding. These findings establish its non-inert profile of tissue-specific distribution, innate immune activation, complex metabolism, and plasma protein-based excipient-drug interactions, highlighting DSPE-PEG2000's potential safety risks. The innovative methodology developed herein provides a paradigm for polymer tracking and offers critical insights to guide excipient safety assessments and optimization.
{"title":"Deciphering the in vivo fate and biomacromolecular interactions of DSPE-PEG2000","authors":"Deqi Cai , Chong Su , Mingyang Zhao , Huan Yang , Zhe Zhang , Yingze Liu , Jingkai Gu","doi":"10.1016/j.jconrel.2025.114571","DOIUrl":"10.1016/j.jconrel.2025.114571","url":null,"abstract":"<div><div>DSPE-PEG2000 (1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-poly(ethylene glycol)-2000), a key excipient of stealth nano-formulations like Doxil®, prolongs nano-carrier blood residence by forming steric hydrophilic barriers. However, its assumed biological inertness faces challenges from emerging PEG-related risks. Limited by analytical methods, its <em>in vivo</em> fate and biomacromolecular interactions remain uncharacterized. Here, Liquid Chromatography-Quadrupole/Time-of-Flight Mass Spectrometry (LC-Q-TOF MS) and anti-PEG single-chain variable fragment (PEG-scFv) strategy were innovatively employed to decode DSPE-PEG2000's biological properties post-intravenous administration. Results reveal a short plasma half-life, tissue-specific distribution in lung, liver, and spleen, complement activation without adaptive antibody response, cleavage to DSPE/PEG2000 with renal excretion/degradation of PEG2000, and a plasma protein binding rate (PPB) of 63.2 ± 7.11 % that competitively displaces 50 % of doxorubicin binding. These findings establish its non-inert profile of tissue-specific distribution, innate immune activation, complex metabolism, and plasma protein-based excipient-drug interactions, highlighting DSPE-PEG2000's potential safety risks. The innovative methodology developed herein provides a paradigm for polymer tracking and offers critical insights to guide excipient safety assessments and optimization.</div></div>","PeriodicalId":15450,"journal":{"name":"Journal of Controlled Release","volume":"390 ","pages":"Article 114571"},"PeriodicalIF":11.5,"publicationDate":"2025-12-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145801382","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}
Boron neutron capture therapy (BNCT) requires the selective delivery of sufficient amounts of 10B to tumors. However, its clinical efficacy remains limited because the approved 10B agent L-4‑boronophenylalanine (BPA) relies primarily on the L-type amino acid transporter 1 (LAT1), leaving LAT1-low tumors refractory to treatment. Here, we report GluB-2, a water-soluble, alanine-serine-cysteine transporter 2 (ASCT2)-targeted small-molecule 10B carrier that expands BNCT applicability beyond BPA. GluB-2 exhibited high solubility, low cytotoxicity, and preferential ASCT2-mediated uptake in multiple cancer cell lines, particularly those with low LAT1 and high ASCT2 expression. In vivo, GluB-2 achieved tumor boron concentrations exceeding the therapeutic threshold (>20 μg [10B]/g tissue) after both intravenous and intraperitoneal administration, representing the first non-BPA small-molecule 10B carrier to reach this level. Upon thermal neutron irradiation, GluB-2 induced pronounced tumor suppression in both the CT26 allograft and the BPA-refractory U87MG xenograft models without evidence of systemic toxicity. These findings demonstrate that GluB-2 enables therapeutic small-molecule delivery of 10B to tumors through multiple dosing routes and expands the clinical applicability of BNCT beyond BPA, highlighting its translational potential.
{"title":"Alanine-serine-cysteine transporter-targeted small-molecule boron carriers for neutron capture therapy of L-4‑boronophenylalanine-refractory tumors","authors":"Kazuki Miura , Tomoyuki Araki , Taiki Morita , Kai Nishimura , Satoshi Okada , Minoru Suzuki , Hiroyuki Nakamura","doi":"10.1016/j.jconrel.2025.114566","DOIUrl":"10.1016/j.jconrel.2025.114566","url":null,"abstract":"<div><div>Boron neutron capture therapy (BNCT) requires the selective delivery of sufficient amounts of <sup>10</sup>B to tumors. However, its clinical efficacy remains limited because the approved <sup>10</sup>B agent L-4‑boronophenylalanine (BPA) relies primarily on the L-type amino acid transporter 1 (LAT1), leaving LAT1-low tumors refractory to treatment. Here, we report <strong>GluB-2</strong>, a water-soluble, alanine-serine-cysteine transporter 2 (ASCT2)-targeted small-molecule <sup>10</sup>B carrier that expands BNCT applicability beyond BPA. <strong>GluB-2</strong> exhibited high solubility, low cytotoxicity, and preferential ASCT2-mediated uptake in multiple cancer cell lines, particularly those with low LAT1 and high ASCT2 expression. <em>In vivo</em>, <strong>GluB-2</strong> achieved tumor boron concentrations exceeding the therapeutic threshold (>20 μg [<sup>10</sup>B]/g tissue) after both intravenous and intraperitoneal administration, representing the first non-BPA small-molecule <sup>10</sup>B carrier to reach this level. Upon thermal neutron irradiation, <strong>GluB-2</strong> induced pronounced tumor suppression in both the CT26 allograft and the BPA-refractory U87MG xenograft models without evidence of systemic toxicity. These findings demonstrate that <strong>GluB-2</strong> enables therapeutic small-molecule delivery of <sup>10</sup>B to tumors through multiple dosing routes and expands the clinical applicability of BNCT beyond BPA, highlighting its translational potential.</div></div>","PeriodicalId":15450,"journal":{"name":"Journal of Controlled Release","volume":"390 ","pages":"Article 114566"},"PeriodicalIF":11.5,"publicationDate":"2025-12-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145801493","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 : 2025-12-21DOI: 10.1016/j.jconrel.2025.114563
Yao Li , Shiman Yuan , Cong Zhang , Pengcheng Hu , Xiaoying Huang , Jialin Zhou , Danning Liu , Xiyuan Zhou
Dry age-related macular degeneration (dAMD) is a leading cause of irreversible blindness, driven by oxidative stress-induced retinal pigment epithelial (RPE) cell degeneration. Existing therapies suffer from poor bioavailability and insufficient multi-pathway modulation. To address this, we developed P(R)/T-Lf nanoparticles, a subconjunctivally administered nanotherapy co-loaded with resveratrol (Res) and dual-functionalized with trimethyl chitosan (TMC) and lactoferrin (Lf). The P(R)/T-Lf NPs exhibited: (1) prolonged ocular retention via TMC-mediated mucoadhesion and enhanced RPE targeting through Lf receptor binding; (2) sustained Res release over 35 days, effectively scavenging reactive oxygen species and inhibiting ferroptosis by downregulating NOX2, ACSL4, and COX2 while restoring GPX4; (3) superior therapeutic outcomes in NaIO₃-induced dAMD models, preserving retinal morphology and function. Comparative studies demonstrated that P(R)/T-Lf NPs outperformed non-targeted controls. This nanoplatform provides a translation-ready strategy to concurrently tackle oxidative stress, inflammation, and ferroptosis via sustained, targeted delivery, representing a transformative approach for dAMD therapy.
{"title":"Engineered nanoparticles for subconjunctival delivery to the retinal pigment epithelium: A multi-target therapy for dry AMD","authors":"Yao Li , Shiman Yuan , Cong Zhang , Pengcheng Hu , Xiaoying Huang , Jialin Zhou , Danning Liu , Xiyuan Zhou","doi":"10.1016/j.jconrel.2025.114563","DOIUrl":"10.1016/j.jconrel.2025.114563","url":null,"abstract":"<div><div>Dry age-related macular degeneration (dAMD) is a leading cause of irreversible blindness, driven by oxidative stress-induced retinal pigment epithelial (RPE) cell degeneration. Existing therapies suffer from poor bioavailability and insufficient multi-pathway modulation. To address this, we developed P(R)/T-Lf nanoparticles, a subconjunctivally administered nanotherapy co-loaded with resveratrol (Res) and dual-functionalized with trimethyl chitosan (TMC) and lactoferrin (Lf). The P(R)/T-Lf NPs exhibited: (1) prolonged ocular retention via TMC-mediated mucoadhesion and enhanced RPE targeting through Lf receptor binding; (2) sustained Res release over 35 days, effectively scavenging reactive oxygen species and inhibiting ferroptosis by downregulating NOX2, ACSL4, and COX2 while restoring GPX4; (3) superior therapeutic outcomes in NaIO₃-induced dAMD models, preserving retinal morphology and function. Comparative studies demonstrated that P(R)/T-Lf NPs outperformed non-targeted controls. This nanoplatform provides a translation-ready strategy to concurrently tackle oxidative stress, inflammation, and ferroptosis via sustained, targeted delivery, representing a transformative approach for dAMD therapy.</div></div>","PeriodicalId":15450,"journal":{"name":"Journal of Controlled Release","volume":"390 ","pages":"Article 114563"},"PeriodicalIF":11.5,"publicationDate":"2025-12-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145813471","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 : 2025-12-20DOI: 10.1016/j.jconrel.2025.114562
Zijuan Wang , Yuanzhen Su , Shucheng Zhang , Bingzheng Yu , Dongbo Chen , Xiang Gao , Yan Wei , Irina A. Veselova , Mingqiang Li , Shixian Lv
Tumor vaccines hold significant promise for immunotherapy, but are limited by low antigen loading capacity, inefficient cytosolic delivery, and suboptimal T cell activation. Here, we present an octopus-inspired polymeric nanovaccine that integrates high antigen-loading capacity and effective cytosolic delivery within a single polymeric platform. The nanovaccine is constructed by encapsulating antigens with an imidazole-functionalized fluorinated polyethyleneimine and Mn2+ ions, forming a structure that mimics octopus tentacles and suction cups, where the PEI backbone acts as tentacle-like arms and the imidazole-Mn2+ units serve as suction cups. This multivalent interface enables robust antigen binding through electrostatic, coordination, and hydrophobic interactions. Beyond stabilizing the antigen payload, the amphiphilic cationic design of the polymers offers efficient cytosolic delivery of antigens into dendritic cells (DCs). Meanwhile, the intracellular release of Mn2+ activates the STING pathway, promoting innate immune responses. Consequently, the vaccine elicits robust antigen-specific CD8+ T cell responses and durable antitumor immunity in multiple tumor models. This work presents a streamlined, multifunctional strategy to overcome delivery barriers in cancer vaccines.
{"title":"Octopus-inspired polymeric nanovaccine enables high antigen loading and robust T cell activation for cancer immunotherapy","authors":"Zijuan Wang , Yuanzhen Su , Shucheng Zhang , Bingzheng Yu , Dongbo Chen , Xiang Gao , Yan Wei , Irina A. Veselova , Mingqiang Li , Shixian Lv","doi":"10.1016/j.jconrel.2025.114562","DOIUrl":"10.1016/j.jconrel.2025.114562","url":null,"abstract":"<div><div>Tumor vaccines hold significant promise for immunotherapy, but are limited by low antigen loading capacity, inefficient cytosolic delivery, and suboptimal T cell activation. Here, we present an octopus-inspired polymeric nanovaccine that integrates high antigen-loading capacity and effective cytosolic delivery within a single polymeric platform. The nanovaccine is constructed by encapsulating antigens with an imidazole-functionalized fluorinated polyethyleneimine and Mn<sup>2+</sup> ions, forming a structure that mimics octopus tentacles and suction cups, where the PEI backbone acts as tentacle-like arms and the imidazole-Mn<sup>2+</sup> units serve as suction cups. This multivalent interface enables robust antigen binding through electrostatic, coordination, and hydrophobic interactions. Beyond stabilizing the antigen payload, the amphiphilic cationic design of the polymers offers efficient cytosolic delivery of antigens into dendritic cells (DCs). Meanwhile, the intracellular release of Mn<sup>2+</sup> activates the STING pathway, promoting innate immune responses. Consequently, the vaccine elicits robust antigen-specific CD8<sup>+</sup> T cell responses and durable antitumor immunity in multiple tumor models. This work presents a streamlined, multifunctional strategy to overcome delivery barriers in cancer vaccines.</div></div>","PeriodicalId":15450,"journal":{"name":"Journal of Controlled Release","volume":"390 ","pages":"Article 114562"},"PeriodicalIF":11.5,"publicationDate":"2025-12-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145796069","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 : 2025-12-20DOI: 10.1016/j.jconrel.2025.114564
Sydney N. Wheeler , Mary E. Dickenson , Connor N. Joyce , Samantha N. Lukpat , Leon J.M.W. Wagner , Andrés R. Muñoz-Rojas , Aaron H. Morris
A thorough understanding of T-cell dynamics and interactions could improve patient care in autoimmunity, cancer immunotherapy, and myriad other conditions, yet monitoring antigen-specific T-cell clones is challenging. T-cells recognize antigens presented by antigen-presenting cells (APCs) in the context of major histocompatibility complexes (MHCs). Specific T-cell clones are rare in the blood (<1 in 100,000), and thus cell expansion which consequently alters cell phenotype and function is typically necessary before analysis. This motivates the development of new methods for enriching T-cell populations of interest without phenotypically altering them. Recent work has demonstrated that implantable biomaterial systems can recruit disease-relevant cells in autoimmune conditions, and that if antigens are present, antigen-specific T-cells become enriched in these materials. To date, antigen-loaded materials have exhibited uncontrolled loading, burst release, and subsequent T-cell exhaustion. In this report, we engineer a novel biomaterial antigen delivery system by conjugating antigens to the polymer backbone prior to porous scaffold fabrication. We demonstrate that this technique enables precise antigen loading via ratiometric mixing of modified and unmodified polymer. We show controlled release of antigen into the microenvironment and demonstrate that released antigen is processed and presented by APCs. Using this fabrication method, we achieve sustained release of peptide antigens over a period of 3 weeks in vitro. When implanted in healthy mice, these antigen-conjugated scaffolds are invaded by host myeloid and lymphoid cells and exhibit a dose-dependent enrichment of systemically circulating antigen-specific T-cell populations, while avoiding significant T-cell exhaustion. Finally, we apply this system to an autoantigen from multiple sclerosis (MS) and show release and interaction with autoantigen-specific T-cells. Using this technique, disease-relevant T-cells can be recruited for diagnostic assessment or for immunological research. Future work will investigate the potential of these systems to monitor disease onset and progression in vivo, co-deliver multiple antigens for assessment of epitope spreading, therapeutically target disease-relevant cells within a local niche in situ, and expand the platform for controlled delivery of therapeutic peptides in models beyond autoimmunity.
{"title":"Antigen-conjugated scaffolds enable sustained delivery of antigen and enrichment of antigen-specific T-cells","authors":"Sydney N. Wheeler , Mary E. Dickenson , Connor N. Joyce , Samantha N. Lukpat , Leon J.M.W. Wagner , Andrés R. Muñoz-Rojas , Aaron H. Morris","doi":"10.1016/j.jconrel.2025.114564","DOIUrl":"10.1016/j.jconrel.2025.114564","url":null,"abstract":"<div><div>A thorough understanding of T-cell dynamics and interactions could improve patient care in autoimmunity, cancer immunotherapy, and myriad other conditions, yet monitoring antigen-specific T-cell clones is challenging. T-cells recognize antigens presented by antigen-presenting cells (APCs) in the context of major histocompatibility complexes (MHCs). Specific T-cell clones are rare in the blood (<1 in 100,000), and thus cell expansion which consequently alters cell phenotype and function is typically necessary before analysis. This motivates the development of new methods for enriching T-cell populations of interest without phenotypically altering them. Recent work has demonstrated that implantable biomaterial systems can recruit disease-relevant cells in autoimmune conditions, and that if antigens are present, antigen-specific T-cells become enriched in these materials. To date, antigen-loaded materials have exhibited uncontrolled loading, burst release, and subsequent T-cell exhaustion. In this report, we engineer a novel biomaterial antigen delivery system by conjugating antigens to the polymer backbone prior to porous scaffold fabrication. We demonstrate that this technique enables precise antigen loading <em>via</em> ratiometric mixing of modified and unmodified polymer. We show controlled release of antigen into the microenvironment and demonstrate that released antigen is processed and presented by APCs. Using this fabrication method, we achieve sustained release of peptide antigens over a period of 3 weeks <em>in vitro</em>. When implanted in healthy mice, these antigen-conjugated scaffolds are invaded by host myeloid and lymphoid cells and exhibit a dose-dependent enrichment of systemically circulating antigen-specific T-cell populations, while avoiding significant T-cell exhaustion. Finally, we apply this system to an autoantigen from multiple sclerosis (MS) and show release and interaction with autoantigen-specific T-cells. Using this technique, disease-relevant T-cells can be recruited for diagnostic assessment or for immunological research. Future work will investigate the potential of these systems to monitor disease onset and progression <em>in vivo</em>, co-deliver multiple antigens for assessment of epitope spreading, therapeutically target disease-relevant cells within a local niche <em>in situ</em>, and expand the platform for controlled delivery of therapeutic peptides in models beyond autoimmunity.</div></div>","PeriodicalId":15450,"journal":{"name":"Journal of Controlled Release","volume":"390 ","pages":"Article 114564"},"PeriodicalIF":11.5,"publicationDate":"2025-12-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145796070","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 : 2025-12-20DOI: 10.1016/j.jconrel.2025.114559
Ilaria Facchi , Nicola Di Trani , Camden Caffey , Thi Thao Linh Nguyen , Yongbin Liu , Junjun Zheng , Junhua Mai , Fernanda P. Pons-Faudoa , Yitian Xu , Shu-Hsia Chen , Jason T. Kimata , Joan E. Nichols , Corrine Ying Xuan Chua , Alessandro Grattoni
Long-acting antiretroviral therapy (LA-ART) holds promise for improving adherence and viral suppression in human immunodeficiency virus (HIV) prevention and treatment, respectively. These LA-ART encompass different delivery modalities such as intravaginal rings, subcutaneous implants, and intramuscular or subcutaneous injectables. However, subcutaneous implants, especially those containing tenofovir alafenamide (TAF), can trigger local inflammation. In this study, we incorporated MCC950, a selective NLRP3 (NOD-, LRR-, and pyrin domain-containing protein 3) inhibitor, into a subcutaneous nanofluidic implant co-delivering TAF and bictegravir (BIC). In a rodent model, MCC950 reduced local inflammation, fibrotic capsule formation, and inflammatory cell infiltration without affecting the antiviral activity of TAF or BIC. Sustained plasma levels of both drugs were maintained for up to 45 days, and imaging mass cytometry and histological analyses confirmed localized immunomodulation. These findings establish inflammasome inhibition as a viable strategy to improve the safety and tolerability of subcutaneous LA-ART and lay the groundwork for future immunomodulatory-enhanced drug delivery systems.
{"title":"Localized inflammasome inhibition mitigates foreign body response to subcutaneous long-acting antiretroviral therapy for HIV","authors":"Ilaria Facchi , Nicola Di Trani , Camden Caffey , Thi Thao Linh Nguyen , Yongbin Liu , Junjun Zheng , Junhua Mai , Fernanda P. Pons-Faudoa , Yitian Xu , Shu-Hsia Chen , Jason T. Kimata , Joan E. Nichols , Corrine Ying Xuan Chua , Alessandro Grattoni","doi":"10.1016/j.jconrel.2025.114559","DOIUrl":"10.1016/j.jconrel.2025.114559","url":null,"abstract":"<div><div>Long-acting antiretroviral therapy (LA-ART) holds promise for improving adherence and viral suppression in human immunodeficiency virus (HIV) prevention and treatment, respectively. These LA-ART encompass different delivery modalities such as intravaginal rings, subcutaneous implants, and intramuscular or subcutaneous injectables. However, subcutaneous implants, especially those containing tenofovir alafenamide (TAF), can trigger local inflammation. In this study, we incorporated MCC950, a selective NLRP3 (NOD-, LRR-, and pyrin domain-containing protein 3) inhibitor, into a subcutaneous nanofluidic implant co-delivering TAF and bictegravir (BIC). In a rodent model, MCC950 reduced local inflammation, fibrotic capsule formation, and inflammatory cell infiltration without affecting the antiviral activity of TAF or BIC. Sustained plasma levels of both drugs were maintained for up to 45 days, and imaging mass cytometry and histological analyses confirmed localized immunomodulation. These findings establish inflammasome inhibition as a viable strategy to improve the safety and tolerability of subcutaneous LA-ART and lay the groundwork for future immunomodulatory-enhanced drug delivery systems.</div></div>","PeriodicalId":15450,"journal":{"name":"Journal of Controlled Release","volume":"390 ","pages":"Article 114559"},"PeriodicalIF":11.5,"publicationDate":"2025-12-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145796073","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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