Journal of Controlled Release最新文献

{"title":"Extracellular vesicles from hypoxia preconditioned bone marrow mesenchymal stem cell improve peri-implant osteogenesis under type 2 diabetes condition","authors":"Xi-Meng Cao ,&nbsp;Ya-Qin Wu ,&nbsp;Ying-Yi Shen ,&nbsp;Zi-Hang Xu ,&nbsp;Xin-Yu Zhang ,&nbsp;Zhen Fan ,&nbsp;Fang Qu ,&nbsp;Chun Xu","doi":"10.1016/j.jconrel.2025.114276","DOIUrl":"10.1016/j.jconrel.2025.114276","url":null,"abstract":"<div><h3>Purpose</h3><div>Poor peri-implant osseointegration of dental implants in patients with type 2 diabetes has become a major clinical challenge in recent years. BMSC (bone marrow mesenchymal stem cell)-derived extracellular vesicles may play an important role in peri-implant osseointegration, but the mechanism remains unclear. Improving the therapeutic effect of BMSC-derived extracellular vesicles and exploring their potential mechanisms can help provide new treatment strategies for dental implants in patients with type 2 diabetes.</div></div><div><h3>Methods</h3><div>The extracellular vesicles derived from hypoxia (Hypo-EVs) or normoxia (Nor-EVs) preconditioned bone marrow mesenchymal stem cells (BMSCs) were co-cultured with BMSCs and human umbilical vein endothelial cells (HUVECs). The effect of extracellular vesicles on BMSCs cell proliferation was detected by CCK-8 assay and EdU assay, and the effect on angiogenesis ability of HUVECs was detected by wound healing assay, transwell migration assay, tube formation assay, enzyme-linked immunosorbent assay (ELISA), quantitative real-time polymerase chain reaction (qRT-PCR) and western blot. A diabetic rat dental implant model was also established and the effect of extracellular vesicles on implant osseointegration was evaluated through micro-CT scanning and histological analysis. The differentially expressed miRNAs between Hypo-EVs and Nor-EVs were identified by high-throughput miRNA sequencing. Subsequently, the target genes and their roles in regulating angiogenesis were predicted and analyzed by bioinformatics analysis and dual luciferase reporter assay.</div></div><div><h3>Results</h3><div>In vitro experiments indicated that hypoxia preconditioning could elevate extracellular vesicle production and promote cell proliferation of BMSCs and angiogenesis of HUVECs. Moreover, Hypo-EVs promoted peri-implant osteogenesis in rats with diabetes. Further investigation revealed the vital involvement of the miR-106b-5p/HIF-1α axis in promoting peri-implant osseointegration under high glucose condition.</div></div><div><h3>Conclusion</h3><div>Extracellular vesicles derived from hypoxia-preconditioned BMSCs could improve the peri-implant osseointegration in rats with diabetes by promoting cell proliferation and angiogenesis, and the miR-106b-5p/ HIF-1α axis could be the underlying mechanism.</div></div>","PeriodicalId":15450,"journal":{"name":"Journal of Controlled Release","volume":"388 ","pages":"Article 114276"},"PeriodicalIF":11.5,"publicationDate":"2025-09-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145153603","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":"Glycoliposomes target lymphatic dendritic cells in a size-dependent manner to activate natural killer T cells against breast tumors","authors":"Taehun Hong ,&nbsp;Keita Masuda ,&nbsp;Yuki Nakashima ,&nbsp;Shangwei Li ,&nbsp;Pengwen Chen ,&nbsp;Guanghao Hu ,&nbsp;Kazunori Igarashi ,&nbsp;Ayumi Kimura ,&nbsp;Koji Fujita ,&nbsp;Tomohiro Umezu ,&nbsp;Masahiko Kuroda ,&nbsp;Horacio Cabral","doi":"10.1016/j.jconrel.2025.114274","DOIUrl":"10.1016/j.jconrel.2025.114274","url":null,"abstract":"<div><div>Glycolipids have high potential for activating natural killer T (NKT) cells to mediate robust antitumor responses. However, critical challenges, such as low baseline NKT cell counts and the risk of unintentionally engaging immunosuppressive NKT subsets that dampen immune activation, have limited their clinical efficacy. Because antitumor NKT cells are functionalized by dendritic cells (DCs) in lymph nodes, targeting these cells is the key to selective antitumor NKT activation. Here, we developed size-modulated glycoliposomes using the potent glycolipid RK-163 (RK) for selectively targeting lymphatic DCs and promoting strong antitumor efficacy. Our results showed that RK glycoliposomes (RK-lipo) with 100 nm diameter achieved superior lymph node accumulation and DC uptake, leading to high IFN-γ secretion, expansion of NKT cell populations in lymph nodes, and reduction of anti-inflammatory signals. Furthermore, we confirmed an increased level of NKT cells in tumors after treatment with 100 nm RK-lipo, enhancing antitumor immunity in a triple-negative breast cancer (TNBC) murine model. Thus, the 100 nm RK-lipo suppressed the growth of orthotopic breast tumors, significantly extending survival with reduced adverse effects. These findings support the potential of targeting DCs with glycoliposomes to promote NKT cell activation, which provides a promising strategy for effective anti-tumor immunotherapy.</div></div>","PeriodicalId":15450,"journal":{"name":"Journal of Controlled Release","volume":"388 ","pages":"Article 114274"},"PeriodicalIF":11.5,"publicationDate":"2025-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145140541","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":"Interstitial drug delivery system: Physiological basis and (pre)clinical progress","authors":"Aocan Zhao ,&nbsp;Yisi Tang ,&nbsp;Xudong Shi ,&nbsp;Wufa Fan","doi":"10.1016/j.jconrel.2025.114275","DOIUrl":"10.1016/j.jconrel.2025.114275","url":null,"abstract":"<div><div>The interstitial drug delivery system, with a long-standing history in pharmaceutical science, has recently regained significant attention due to its pivotal role in enhancing drug transport to lymphatic vessels and improving lymph node targeting. The success of mRNA vaccines against SARS-CoV-2 during the COVID-19 pandemic has ushered in a new era for interstitial-based drug delivery strategies. Consequently, advancing the development of next-generation interstitial delivery systems necessitates a deeper understanding of interstitial physiology. This review systematically summarizes the physiological composition and functions of the interstitium, discusses the distinct characteristics of diverse interstitial administration routes, evaluates recent advances in formulation design and clinical translation efforts of advanced delivery systems, and highlights current challenges and future directions in the field. By providing this comprehensive analysis, we aim to stimulate the wider clinical application of interstitial delivery systems in therapeutic practice.</div></div>","PeriodicalId":15450,"journal":{"name":"Journal of Controlled Release","volume":"388 ","pages":"Article 114275"},"PeriodicalIF":11.5,"publicationDate":"2025-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145153605","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":"Engineering unnatural amino acids in peptide linkers enables cathepsin-selective antibody-drug conjugates for HER2-positive breast cancer","authors":"Oliwia Gorzeń ,&nbsp;Maria Łęcka ,&nbsp;Natalia Ćwilichowska-Puślecka ,&nbsp;Martyna Majchrzak ,&nbsp;Natalia Horbach ,&nbsp;Jerzy Wiśniewski ,&nbsp;Piotr Jakimowicz ,&nbsp;Paweł Szpot ,&nbsp;Marcin Zawadzki ,&nbsp;Bartosz Dołęga-Kozierowski ,&nbsp;Piotr Kasprzak ,&nbsp;Boris Turk ,&nbsp;Marcin Drąg ,&nbsp;Katarzyna M. Groborz ,&nbsp;Rafał Matkowski ,&nbsp;Marcin Poręba","doi":"10.1016/j.jconrel.2025.114269","DOIUrl":"10.1016/j.jconrel.2025.114269","url":null,"abstract":"<div><div>Antibody-drug conjugates (ADCs) are a rapidly evolving class of targeted cancer therapeutics that combine the specificity of monoclonal antibodies with the potent cytotoxicity of small-molecule payloads. Their clinical success has led to significant advances in oncology, positioning ADCs as a transformative modality in cancer treatment. Most clinically approved ADCs utilize a protease-cleavable valine-citrulline (Val-Cit) dipeptide linker designed to facilitate intracellular payload release upon proteolytic activation by the lysosomal cathepsins. However, the Val-Cit linker is susceptible to off-target cleavage by proteases expressed in non-malignant tissues, resulting in premature payload release and systemic toxicity. To address this limitation, we established a high-throughput peptide linker discovery platform using Hybrid Combinatorial Substrate Library (HyCoSuL) screening to comprehensively profile protease substrate preferences. By incorporating unnatural amino acids, we identified peptide sequences with high selectivity toward cancer-associated proteases, thereby overcoming the constraints of conventional linker design. As proof of concept, we engineered trastuzumab-based ADCs selectively activated by cathepsin B or cathepsin L and evaluated their cytotoxic efficacy in HER2-positive breast cancer models. Our HyCoSuL-guided linkers display higher selectivity toward cathepsins than Val-Cit and enable faster, protease-dependent activation of peptide prodrugs and ADCs in vitro<em>,</em> while also exhibiting enhanced stability in human plasma to minimize premature payload release. Furthermore, recognizing that efficient protease-activated ADC function requires co-expression of both the target antigen and the activating protease, we performed single-cell mass cytometry analysis of patient-derived breast cancer samples to assess the correlation between HER2 and cathepsin expression. This analysis revealed heterogeneous cathepsin expression, underscoring that pairing the antibody target with the appropriate protease-selective linker might critical for robust, tumor-confined payload release. Our findings highlight the importance of patient stratification based on antigen and protease expression profiles, providing a foundation for developing ADCs with greater protease selectivity and minimized off-target activation.</div></div><div><h3>Significance</h3><div>This work presents a rational chemistry-driven strategy using unnatural amino acids to engineer peptide linkers with high cysteine cathepsins specificity and enhanced stability in human plasma. By combining comprehensive enzymatic profiling with single-cell CyTOF analysis of patient tumors, we outline a framework for precision-guided ADC design and protease-informed patient stratification in HER2-positive breast cancer.</div></div>","PeriodicalId":15450,"journal":{"name":"Journal of Controlled Release","volume":"387 ","pages":"Article 114269"},"PeriodicalIF":11.5,"publicationDate":"2025-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145134382","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":"Hydroxychloroquine-functionalized ionizable lipids mitigate inflammatory responses in mRNA therapeutics","authors":"Kepan Chen ,&nbsp;Xuechun Li ,&nbsp;Shuo Feng ,&nbsp;Ye Li ,&nbsp;Ting Jiang ,&nbsp;Yan Liu ,&nbsp;Na Guo ,&nbsp;Xiaoling Zeng ,&nbsp;Hongwei Yao ,&nbsp;Min Qiu ,&nbsp;Jing Lu ,&nbsp;Jinzhong Lin","doi":"10.1016/j.jconrel.2025.114267","DOIUrl":"10.1016/j.jconrel.2025.114267","url":null,"abstract":"<div><div>Lipid nanoparticle (LNP)-based mRNA therapeutics, highlighted by the success of SARS-CoV-2 vaccines, face challenges due to inflammation caused by ionizable lipids. These ionizable lipids can activate the immune system, particularly when co-delivered with nucleic acids, leading to undesirable inflammatory responses. We introduce a novel class of anti-inflammatory ionizable lipids functionalized with hydroxychloroquine (HCQ), which suppresses both lipid-induced and nucleic acid-induced immune activation. These HCQ-functionalized LNPs (HL LNPs) exhibit reduced proinflammatory responses while maintaining efficient mRNA delivery. Structural and physicochemical analyses revealed that HCQ-functionalization results in a distinct particle structure with significantly improved stability. The efficacy of HL LNPs was demonstrated across various therapeutic contexts, including a prophylactic vaccination model against varicella-zoster virus (VZV) and CRISPR-Cas9 gene editing targeting PCSK9. Notably, HL LNPs showed robust mRNA expression after repeated administration, addressing concerns of inflammation and ensuring sustained therapeutic effects. These findings highlight the potential of HCQ-functionalized LNPs in expanding the safe use of mRNA therapeutics, particularly for applications requiring repeated dosing and in scenarios where inflammation-induced side effects must be minimized.</div></div>","PeriodicalId":15450,"journal":{"name":"Journal of Controlled Release","volume":"387 ","pages":"Article 114267"},"PeriodicalIF":11.5,"publicationDate":"2025-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145134372","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":"Horizontal blocking of metastatic growth factors signaling by low molecular weight heparin derivative to control ovarian cancer progression","authors":"Farzana Alam ,&nbsp;Mohammad R. Haque ,&nbsp;Jeong Uk Choi ,&nbsp;Shriya Roy ,&nbsp;Jee Heon Jeong ,&nbsp;Taslim A. Al-Hilal ,&nbsp;Youngro Byun","doi":"10.1016/j.jconrel.2025.114273","DOIUrl":"10.1016/j.jconrel.2025.114273","url":null,"abstract":"<div><div>Conventional ovarian cancer treatments include surgery, radio/chemotherapy, and targeted therapies aimed at signaling pathways like transforming growth factor-β (TGFβ) and vascular endothelial growth factor (VEGF). However, targeted therapies often fall short due to the activation of alternative pathways and lack of patient responses. Thus, the use of a single targeted therapeutic to block more than one pathway simultaneously, termed as horizontal pathways, is hard to achieve due to their structural rigidity and uniformity. Heparin's vast structural diversity allows it to bind with and regulate many proteins via binding to their heparin-binding domains. Here, we aim to address the limitation of horizontal targeting approach by using a low molecular weight heparin-based compound conjugated with seven taurocholic and tetrameric deoxycholic acids (LHTD4). LHTD4 has shown promise as an orally active anti-angiogenic agent, effectively inhibiting VEGF and TGFβ pathways crucial for ovarian cancer progression. LHTD4 significantly reduced TGFβ and VEGF receptor phosphorylation in SKOV3 cells, attenuated EMT-genes, and suppressed malignant spheroid formation. In mouse models of orthotopic and peritoneal ovarian cancer metastasis, LHTD4 decreased tumor growth and metastasis, prolonged survival, and prevented malignant ascites formation. LHTD4's ability to block horizontal pathways offers a promising therapeutic strategy to halt ovarian cancer metastasis at different stages of progression.</div></div>","PeriodicalId":15450,"journal":{"name":"Journal of Controlled Release","volume":"387 ","pages":"Article 114273"},"PeriodicalIF":11.5,"publicationDate":"2025-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145140543","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":"Enhanced safety and potency in local angiogenic growth factor delivery via aptamer functionalization of hydrogels","authors":"Connie Wen ,&nbsp;Ji Ho Park ,&nbsp;Neekita R. Jikaria ,&nbsp;Mary E. Landmesser ,&nbsp;Jazzmyn Dawes ,&nbsp;Chien-Wei Wu ,&nbsp;Dino Ravnic ,&nbsp;Yong Wang","doi":"10.1016/j.jconrel.2025.114251","DOIUrl":"10.1016/j.jconrel.2025.114251","url":null,"abstract":"<div><div>Hydrogels for drug delivery, particularly for the delivery of potent protein therapeutics, have been extensively studied across various biomedical applications. Because hydrogels act as reservoirs for localized drug release, this delivery approach is generally not expected to cause the same severe systemic toxicity observed with systemic drug administration. However, the current study has shown for the first time that the implantation of native hydrogels loaded with vascular endothelial growth factor (VEGF) induced acute severe hemorrhage and animal mortality in a femoral vessel micropuncture (MP) surgery model. In contrast, no side effects were observed when hydrogels functionalized with anti-VEGF aptamers and loaded with the same amount of VEGF were implanted. Furthermore, the presence of the aptamers in the hydrogels did not compromise the ability of VEGF to promote new blood vessel growth.</div></div>","PeriodicalId":15450,"journal":{"name":"Journal of Controlled Release","volume":"387 ","pages":"Article 114251"},"PeriodicalIF":11.5,"publicationDate":"2025-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145127739","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":"Lipid nanomedicine simultaneously inhibits BRD4/PI3K and MDM2/XIAP signaling pathways for effective treatment of Medulloblastoma","authors":"Bharti Sethi ,&nbsp;Aditya Gupta ,&nbsp;Qiaoyu Pan ,&nbsp;Sohan Mahto ,&nbsp;Ajaykumar Chittipolu ,&nbsp;Helen Erickson ,&nbsp;Virender Kumar ,&nbsp;Yanfei Chen ,&nbsp;Zhongzhi Wu ,&nbsp;Yuxiang Dong ,&nbsp;Wei Li ,&nbsp;Donald R. Ronning ,&nbsp;Donald W. Coulter ,&nbsp;Ram I. Mahato","doi":"10.1016/j.jconrel.2025.114266","DOIUrl":"10.1016/j.jconrel.2025.114266","url":null,"abstract":"<div><div>Medulloblastoma (MB) is the most common childhood brain tumor arising from the cerebellum. PI3K and BRD4 signaling pathways are known to induce MB cell growth, cancer stem cell (CSC) proliferation, and tumor resistance. Further, the tumor suppressor gene <em>TP53</em> is found to be inactivated in MB due to overexpression of its negative regulator MDM2. In this study, we synthesized MDP5, a potent BRD4/PI3K dual inhibitor, and JW475A, a potent dual MDM2 and XIAP inhibitor. The combination of these two drugs significantly decreased the colony formation capacity compared to individual drugs. Given the challenge of inefficient drug transport across the blood-brain barrier (BBB), we prepared rabies virus glycoprotein (RVG) peptide decorated lipid nanoparticles (LNPs), which showed 4.9 ± 0.1 and 4.8 ± 0.1 % loading for MDP5 and JW475A, respectively. In vivo studies in mice showed that Cy5.5 labeled RVG-LNPs were detected in the brain after systemic administration. Combination drug-loaded RVG-LNPs significantly decreased the MB growth in orthotopic mouse model of MB compared to free drug combination and non-targeted LNPs. This study indicates that MDP5 and JW475A -loaded RVG-LNPs are a promising drug brain delivery system worth exploring further in clinical settings for MB therapy.</div></div>","PeriodicalId":15450,"journal":{"name":"Journal of Controlled Release","volume":"387 ","pages":"Article 114266"},"PeriodicalIF":11.5,"publicationDate":"2025-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145134373","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":"Encapsulation-enhanced switchable protein release from engineered probiotic lactobacilli","authors":"Marc Blanch-Asensio ,&nbsp;Varun Sai Tadimarri ,&nbsp;Roberto Martinez ,&nbsp;Gurvinder Singh Dahiya ,&nbsp;Cao Nguyen Duong ,&nbsp;Rahmi Lale ,&nbsp;Shrikrishnan Sankaran","doi":"10.1016/j.jconrel.2025.114264","DOIUrl":"10.1016/j.jconrel.2025.114264","url":null,"abstract":"<div><div>Living microbial therapeutics promise precise, programmable interventions at disease sites, yet most demonstrations of on demand drug release still rely on <em>Escherichia coli</em>, whose rich genetic toolkit is unmatched among probiotics. In particular, genetic parts to regulate <em>in situ</em> protein production are severely lacking in non-model probiotic bacteria like lactobacilli. Here, we equip the probiotic <em>Lactiplantibacillus plantarum</em> with high-performance genetic switches and show how material encapsulation can further enhance their behavior. By integrating cumate or vanillate-responsive operators and repressors with the strongest constitutive promoter in <em>L. plantarum</em> (<em>P</em>_<em>tec</em>), we generated two switches that support micromolar range induction. In rapidly growing culture conditions, acidification-associated leakiness of the switch was observed, which could compromise their applicability for precise on-demand delivery of drugs. Furthermore, such leakiness also limits the duration for which these engineered probiotics can be reliably used. By restricting growth through mild temperature or nutrient limitation, acidification and leakiness were suppressed. Strikingly, immobilizing the engineered cells in core-shell alginate beads (Protein Eluting Alginate with Recombinant Lactobacilli, PEARLs) almost eliminated leakiness, enabling day-scale, reversible control of intracellular reporters and secreted enzymes. This leakiness suppression persisted when two strains carrying orthogonal switches were co-encapsulated and even after miniaturization to submillimeter beads. These results expand the genetic toolbox of probiotic <em>L</em>. <em>plantarum</em>, demonstrate the synergy between genetic circuit design and material encapsulation, and advance lactobacilli toward stimuli-responsive therapeutic platforms.</div></div>","PeriodicalId":15450,"journal":{"name":"Journal of Controlled Release","volume":"387 ","pages":"Article 114264"},"PeriodicalIF":11.5,"publicationDate":"2025-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145134381","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":"Development of a dissolving microneedle patch for transdermal delivery of SARS-CoV-2 mRNA vaccine with enhanced stability and immunogenicity","authors":"Zequn Tang ,&nbsp;Tong Su ,&nbsp;Ting Jiang ,&nbsp;Jiayi Hu ,&nbsp;Daiyan Chen ,&nbsp;Xi Li ,&nbsp;Jing Lu ,&nbsp;Jinzhong Lin ,&nbsp;Teng Shen","doi":"10.1016/j.jconrel.2025.114263","DOIUrl":"10.1016/j.jconrel.2025.114263","url":null,"abstract":"<div><div>Microneedles (MNs)-based transdermal delivery systems present a promising alternative to intramuscular injection (IM) for mRNA vaccines, offering improved patient compliance, enhanced skin-targeted delivery, and increased vaccine stability while reducing hepatic accumulation of lipid nanoparticles (LNPs). Here, we developed a dissolving microneedle patch (DMP) for SARS-CoV-2 mRNA vaccine RQ3013 delivery, employing a matrix composed of 15 % polyvinyl alcohol (PVA) and 10 % polyvinylpyrrolidone (PVP) for its optimal mechanical properties and mRNA-LNPs compatibility. We utilized the one-step vacuum micro-molding process to fabricate DMP loaded with mRNA-LNPs, which significantly improved the encapsulation efficiency of mRNA-LNPs in MNs from 72.34 ± 1.44 % (two-step vacuum micro-molding process) to 95.54 ± 1.29 %. In vivo imaging revealed that the one-step DMP achieved 2.2-fold higher cumulative fluorescence intensity than the two-step DMP and 2.6-fold higher than IM. The DMP preserved the key physicochemical properties and biological functions of mRNA-LNPs, enabling efficient cellular uptake and target antigen expression following successful endosomal escape. Remarkably, the DMP exhibited excellent stability, with no significant changes in key properties after 30 days of storage at room temperature. Notably, the DMP induced a comparable IgG response to IM (5 μg) at a substantially lower actual delivery dose (approximately 2 μg), without systemic toxicity or skin irritation. These findings demonstrate that this DMP represents an effective, stable, and patient-friendly strategy for mRNA vaccine delivery, combining enhanced immunogenicity with improved storage stability and simplified administration.</div></div>","PeriodicalId":15450,"journal":{"name":"Journal of Controlled Release","volume":"388 ","pages":"Article 114263"},"PeriodicalIF":11.5,"publicationDate":"2025-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145127769","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}