Journal of Controlled Release最新文献

{"title":"Engineering sialylated N-glycans on adeno-associated virus capsids for targeted gene delivery and therapeutic applications","authors":"Weixuan Zhao ,&nbsp;Jinhuan Luo ,&nbsp;Fudi Wang ,&nbsp;Yingying Shi ,&nbsp;Jiawen Zhang ,&nbsp;Yuanjie Zhang ,&nbsp;Yingbo Li ,&nbsp;Xinchen Wang ,&nbsp;Yingying Chen ,&nbsp;Xiaohui Zhang ,&nbsp;Xiaoyang Wang ,&nbsp;Yu Mu ,&nbsp;Dezhong Ji ,&nbsp;Sulong Xiao ,&nbsp;Qi Wang ,&nbsp;Lihe Zhang ,&nbsp;Chuanling Zhang ,&nbsp;Demin Zhou","doi":"10.1016/j.jconrel.2025.02.015","DOIUrl":"10.1016/j.jconrel.2025.02.015","url":null,"abstract":"<div><div>Glycans with diverse biological functions have been extensively identified on enveloped viruses, whereas glycosylation on adeno-associated virus (AAV) serotypes remains poorly understood. Identifying potential glycosylation sites on AAVs could provide critical docking sites for rational engineering of AAV capsids, enabling targeted delivery of therapeutic genes. This study presents a strategy that integrates azido-monosaccharide metabolic incorporation, 1,2-diamino-4,5-methylenedioxybenzene-labeled sialic acid analysis, and mass spectrometry to identify N-glycosylation sites and glycoforms on AAVs. We identified sialylated N- oligosaccharides, particularly the conserved NNNS motif, on AAV2, AAV6, AAV7, and AAV9 capsids. These glycans play critical roles in maintaining capsid stability and enhancing resistance to neutralizing antibodies. Furthermore, we engineered an AAV vector with an azido-labeled terminal sialic acid, which was conjugated via click chemistry to cyclic Arg-Gly-Asp (RGD), a high-affinity ligand for integrin αvβ3, to generate an integrin-targeted delivery vehicle. This approach enabled the efficient delivery of c-Met-targeting shRNA in a glioma mouse model and facilitated CRISPR/Cas9-mediated SMOC2 knockout in a mouse model of kidney fibrosis using single-guide RNA (sgRNA). Our findings establish a foundation for creating editable AAV vectors through sialylated termini, thereby expanding their potential applications in basic research and therapeutic development.</div></div>","PeriodicalId":15450,"journal":{"name":"Journal of Controlled Release","volume":"380 ","pages":"Pages 563-578"},"PeriodicalIF":10.5,"publicationDate":"2025-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143402721","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":"Microneedle-based nanodrugs for tumor immunotherapy","authors":"Tianye Wang ,&nbsp;Hongyu Liu ,&nbsp;Meng Li ,&nbsp;Zao Ji ,&nbsp;Xinyuan Zhang ,&nbsp;Nan Wang ,&nbsp;Ying Chen ,&nbsp;Jin Sun ,&nbsp;Funan Liu","doi":"10.1016/j.jconrel.2025.02.003","DOIUrl":"10.1016/j.jconrel.2025.02.003","url":null,"abstract":"<div><div>Microneedles have emerged as a promising and effective method for delivering therapeutic drugs and immunobiologics to treat various diseases. It is widely recognized that immune therapy has limited efficacy in solid tumors due to physical barriers and the immunosuppressive tumor microenvironment. Microneedle-based nanodrugs (NDMNs) offer a novel approach to overcome these limitations. These tiny needles are designed to load a variety of inorganic and organic nanoparticles, antigen vaccines, gene drugs, oncolytic viruses, and more. Utilizing microneedle arrays, NDMNs can effectively penetrate the skin barrier, delivering drugs precisely to the tumor site or immunoactive regions within the skin. Additionally, by designing and optimizing the microneedle structure, shape, and functionality, NDMNs enable precise drug release and efficient penetration, thereby enhancing the efficacy of tumor immunotherapy. In this review, we comprehensively discuss the pivotal role of NDMNs in cancer immunotherapy, summarizing innovative microneedle design strategies, mechanisms of immune activation, and delivery strategies of various nanodrugs. Furthermore, we explore the current clinical realities, limitations, and future prospects of NDMNs in tumor immunotherapy.</div></div>","PeriodicalId":15450,"journal":{"name":"Journal of Controlled Release","volume":"380 ","pages":"Pages 539-562"},"PeriodicalIF":10.5,"publicationDate":"2025-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143382490","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":"Maltodextrin-driven MOF Nano-antibacterial system for effective targeted bacteria and enhancing photodynamic therapy in bacterial keratitis.","authors":"Lifang Chen, Yao Wang, Xiuqing Huang, Lifang Han, Zhengwei Huang, Ling Guo, Kai Chen, Guoxin Tan","doi":"10.1016/j.jconrel.2025.02.031","DOIUrl":"https://doi.org/10.1016/j.jconrel.2025.02.031","url":null,"abstract":"<p><p>The occurrence of bacterial keratitis (BK) presents a significant threat to ocular health, often leading to visual impairment. Currently, conventional antibiotic therapies tend to promote bacterial resistance and lack biocompatibility. Therefore, it is of great significance to develop an alternative product with safe and efficient antimicrobial properties. In this study, we developed a novel smart pH-responsive nano-antibacterial system (PM/Ag-Ce6@ZIF-8) based on a metal-organic framework (MOF), enabling specific bacterial targeting and photodynamic therapy. By utilizing bacteria-specific maltodextrin transport pathway, the intelligent nano-antibacterial modified with maltotriose can accurately discriminate between bacterial infection and normal tissue, specifically target the site of infection, and efficiently accumulate at the infection site to enhance safety and efficacy. Furthermore, the incorporation of silver nanoparticles enhances the effectiveness of MOF photodynamic therapy by effectively eradicating bacteria. The nano-antibacterial system exhibits potent inhibition of biofilm formation as well as antibacterial activity while demonstrating excellent in vitro and in vivo biocompatibility. In an animal model of bacterial keratitis, PM/Ag-Ce6@ZIF-8 exhibits superior antibacterial activity compared to Levofloxacin (LVFX) eye drops, significantly improving therapeutic outcomes for bacterial keratitis in mice. Hence, this intelligent nano-antibacterial platform holds promising potential for clinical applications in treating keratitis.</p>","PeriodicalId":15450,"journal":{"name":"Journal of Controlled Release","volume":" ","pages":""},"PeriodicalIF":10.5,"publicationDate":"2025-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143425425","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":"Receptor-ligand interactions for optimized endocytosis in targeted therapies","authors":"Yejin Sung ,&nbsp;Youngjin Choi ,&nbsp;Eun Sun Kim ,&nbsp;Ju Hee Ryu ,&nbsp;Ick Chan Kwon","doi":"10.1016/j.jconrel.2025.01.060","DOIUrl":"10.1016/j.jconrel.2025.01.060","url":null,"abstract":"<div><div>Receptor-mediated endocytosis plays a crucial role in the success of numerous therapies and remains central to advancing drug development. This process begins with ligand binding to specific receptors, triggering the internalization and intracellular trafficking of receptor-ligand complexes. These complexes are subsequently directed into distinct routes, either toward lysosomal degradation or recycling to the cell surface, with implications for therapeutic outcomes. This review examines receptor-ligand interactions as key modulators of endocytosis, emphasizing their role in shaping therapeutic design and efficacy. Advances in selecting receptor-ligand pairs and engineering ligands with optimized properties have enabled precise control over internalization, endosomal sorting, and trafficking, providing tailored solutions for diverse therapeutic applications. Leveraging these insights, strategies such as RNA-based therapies, antibody-drug conjugates (ADCs), and targeted protein degradation (TPD) platforms have been refined to selectively avoid or promote lysosomal degradation, thereby enhancing therapeutic efficacy. By bridging fundamental mechanisms of receptor-mediated endocytosis with innovative therapeutic approaches, this review offers a framework for advancing precision medicine.</div></div>","PeriodicalId":15450,"journal":{"name":"Journal of Controlled Release","volume":"380 ","pages":"Pages 524-538"},"PeriodicalIF":10.5,"publicationDate":"2025-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143056834","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Drug delivery for platinum therapeutics","authors":"Hui Liu ,&nbsp;Jiahui Zou ,&nbsp;Xiaotong Li ,&nbsp;Yizhi Ge ,&nbsp;Wei He","doi":"10.1016/j.jconrel.2025.02.006","DOIUrl":"10.1016/j.jconrel.2025.02.006","url":null,"abstract":"<div><div>Cancer remains a severe threat to human health. Platinum drugs, such as cisplatin (CDDP), oxaliplatin, and carboplatin, are extensively utilized for treating various cancers and have become the primary drugs in first-line treatments for numerous solid tumors due to their effective anticancer properties. However, their side effects, including drug resistance, nephrotoxicity and ototoxicity, limit the clinical application. Therefore, there is an urgent need to develop targeted delivery and controlled release systems for platinum drugs to address the disadvantages, enhancing tumor accumulation and improving therapeutic effects. In this review, we first review the progress of platinum drugs, their anticancer mechanism, clinical applications and limitations. Then, we comprehensively summarize the platinum-based delivery using drug carriers and responsive strategies. We especially highlight the platinum-delivery formulations in ongoing clinical trials. Finally, we provide perspectives for this field. The review could provide an increasingly in-depth understanding of platinum therapeutics and motivate increasing delivery tactics to overcome the limitations of platinum application.</div></div>","PeriodicalId":15450,"journal":{"name":"Journal of Controlled Release","volume":"380 ","pages":"Pages 503-523"},"PeriodicalIF":10.5,"publicationDate":"2025-02-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143382405","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":"Metabolic reprogramming of macrophages by a nano-sized opsonization strategy to restore M1/M2 balance for osteoarthritis therapy","authors":"Ruijie Chen ,&nbsp;Shimin Zheng ,&nbsp;Xinyu Zhao ,&nbsp;Huirong Huang ,&nbsp;Yitianhe Xu ,&nbsp;Chenyu Qiu ,&nbsp;Shengjie Li ,&nbsp;Xindan Liang ,&nbsp;Pengfei Mao ,&nbsp;Yuqi Yan ,&nbsp;Yinhao Lin ,&nbsp;Shengnan Song ,&nbsp;Wenjing Cai ,&nbsp;Haoxiong Guan ,&nbsp;Yinsha Yao ,&nbsp;Wanling Zhu ,&nbsp;Xianbao Shi ,&nbsp;Vadivel Ganapathy ,&nbsp;Longfa Kou","doi":"10.1016/j.jconrel.2025.02.005","DOIUrl":"10.1016/j.jconrel.2025.02.005","url":null,"abstract":"<div><div>Osteoarthritis is a chronic and progressive joint disease accompanied by cartilage degeneration and synovial inflammation. It is associated with an imbalance of synovial macrophage M1/M2 ratio tilting more towards the pro-inflammatory M1 than the anti-inflammatory M2. The M1-macrophages rely on aerobic glycolysis for energy whereas the M2-macrophages derive energy from oxidative phosphorylation. Therefore, inhibiting aerobic glycolysis to induce metabolic reprogramming of macrophages and consequently promote the shift from M1 type to M2 type is a therapeutic strategy for osteoarthritis. Here we developed a macrophage-targeting strategy based on opsonization, using nanoparticles self-assembled to incorporate Chrysin (an anti-inflammatory flavonoid) and V-9302 (an inhibitor of glutamine uptake), and the outer layer modified by immunoglobulin IgG by electrostatic adsorption into IgG/Fe-CV NPs. In vitro studies showed that IgG/Fe-CV NPs effectively target M1 macrophages and inhibit HIF-1α and GLUT-1 essential for aerobic glycolysis and promote polarization from M1 to M2-type macrophages. In vivo, IgG/Fe-CV NPs inhibit inflammation and protect against cartilage damage. The metabolic reprogramming strategy with IgG/Fe-CV NPs to shift macrophage polarization from inflammatory to anti-inflammatory phenotype by inhibiting aerobic glycolysis and glutamine delivery may open up new avenues to treat osteoarthritis.</div></div>","PeriodicalId":15450,"journal":{"name":"Journal of Controlled Release","volume":"380 ","pages":"Pages 469-489"},"PeriodicalIF":10.5,"publicationDate":"2025-02-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143374174","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":"Crystallization of supersaturated PEG-b-PLA for the production of drug-loaded polymeric micelles","authors":"Morteza Rasoulianboroujeni ,&nbsp;Rae Hyung Kang ,&nbsp;Maraya Klukas ,&nbsp;Glen S. Kwon","doi":"10.1016/j.jconrel.2025.02.009","DOIUrl":"10.1016/j.jconrel.2025.02.009","url":null,"abstract":"<div><div>In this study, we propose the “crystallization from supersaturated solution” method for producing drug-loaded polymeric micelles. This method involves the formation of solid drug-encapsulating crystals of a diblock copolymer through isothermal crystallization from a supersaturated solution of the copolymer in low molecular weight PEGs containing the drug, followed by dissolution of the crystals to obtain drug-loaded micelles. We fabricated and characterized micelles loaded with several model drugs (paclitaxel, rapamycin, and docetaxel) and their oligo(lactic acid)₈-prodrugs using PEG_4kDa-<em>b</em>-PLA_2.2kDa as the micelle-forming copolymer and PEGs of varying molecular weights (200, 400, and 600 Da) as solvents.</div><div>Our findings indicate that the molecular weight of the solvent PEG and the target drug loading significantly influence the physicochemical properties of the resulting micelles, including loading efficiency and particle size distribution. Micelles produced with PEG200 as the solvent exhibited the highest loading efficiency, followed by those made with PEG600 and PEG400 for all the drugs and prodrugs tested. Increasing the target drug loading enhanced both the loading efficiency and average particle size across all formulations. Furthermore, prodrug-loaded micelles showed higher loading efficiency and improved stability in aqueous solutions compared to their parent drug counterparts. Crystals encapsulating both parent drugs and prodrugs could be stored at room temperature for extended periods, producing micelles with no significant differences in loading efficiency and particle size distribution compared to freshly prepared micelles. Additionally, the crystals demonstrated a rapid dissolution rate, forming uniform micelles after just 5 s of hydration and agitation. Cytotoxicity studies against 4 T1 and MDA-MB-231 breast cancer cell lines revealed that the molecular weight of the PEG used as the solvent impacts the cytotoxicity of the resulting micelles, with those produced using PEG200 displaying the highest cytotoxicity, followed by PEG400 and PEG600.</div><div>Overall, the crystallization from supersaturated solution method proves to be an effective platform for prolonged storage and rapid formation of stable, drug-loaded polymeric micelles. It has the potential to eliminate the need for freeze-drying in the formulation and storage of drug-loaded polymeric micelles. These findings highlight the method's potential for advancing drug delivery systems, particularly for the solubilization of hydrophobic drugs using micellar formulations.</div></div>","PeriodicalId":15450,"journal":{"name":"Journal of Controlled Release","volume":"380 ","pages":"Pages 457-468"},"PeriodicalIF":10.5,"publicationDate":"2025-02-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143374161","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":"Cutting-edge biotherapeutics and advanced delivery strategies for the treatment of metabolic dysfunction-associated steatotic liver disease spectrum","authors":"Juhyeong Hong ,&nbsp;Yong-Hee Kim","doi":"10.1016/j.jconrel.2025.02.008","DOIUrl":"10.1016/j.jconrel.2025.02.008","url":null,"abstract":"<div><div>Metabolic dysfunction-associated steatotic liver disease (MASLD), a condition with the potential to progress into liver cirrhosis or hepatocellular carcinoma, has become a significant global health concern due to its increasing prevalence alongside obesity and metabolic syndrome. Despite the promise of existing therapies such as thyroid hormone receptor-β (THR-β) agonists, PPAR agonists, FXR agonists, and GLP-1 receptor agonists, their effectiveness is limited by the complexity of the metabolic, inflammatory, and fibrotic pathways that drive MASLD progression, encompassing steatosis, metabolic dysfunction-associated steatohepatitis (MASH), and reversible liver fibrosis. Recent advances in targeted therapeutics, including RNA interference (RNAi), mRNA-based gene therapies, monoclonal antibodies, proteolysis-targeting chimeras (PROTAC), peptide-based strategies, cell-based therapies such as CAR-modified immune cells and stem cells, and extracellular vesicle-based approaches, have emerged as promising interventions. Alongside these developments, innovative drug delivery systems are being actively researched to enhance the stability, precision, and therapeutic efficacy of these biotherapeutics. These delivery strategies aim to optimize biodistribution, improve target-specific action, and reduce systemic exposure, thus addressing critical limitations of existing treatment modalities. This review provides a comprehensive exploration of the underlying biological mechanisms of MASLD and evaluates the potential of these cutting-edge biotherapeutics in synergy with advanced delivery approaches to address unmet clinical needs. By integrating fundamental disease biology with translational advancements, it aims to highlight future directions for the development of effective, targeted treatments for MASLD and its associated complications.</div></div>","PeriodicalId":15450,"journal":{"name":"Journal of Controlled Release","volume":"380 ","pages":"Pages 433-456"},"PeriodicalIF":10.5,"publicationDate":"2025-02-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143378453","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":"Hydrophobic vehicles for hydrophilic drugs: Sustained intravitreal caffeine delivery with oleogels","authors":"Nan Jiang ,&nbsp;Wei Guo ,&nbsp;Si-yu Wang ,&nbsp;Xin-xin Liu ,&nbsp;Yu-qing Yin ,&nbsp;Ke-xin Xiong ,&nbsp;Xiang-yu Li ,&nbsp;Cheng Liu ,&nbsp;Kai-hui Nan ,&nbsp;Jiang-fan Chen ,&nbsp;Jing-jie Wang","doi":"10.1016/j.jconrel.2025.02.004","DOIUrl":"10.1016/j.jconrel.2025.02.004","url":null,"abstract":"<div><div>Caffeine is the most widely consumed bioactive ingredient in the world, which has been found to show great therapeutic potential in several posterior eye diseases. While intravitreal injection represents the ideal administration route for these disorders, it remains challenging to achieve sustained release of caffeine in the vitreous. Herein, we address this issue by loading crystalline caffeine within oleogels (Ca@oleogels), oily delivery vehicles which provide a hydrophobic environment that is opposite to the hydrophilic nature of their cargos. Mathematical modeling of the <em>in vitro</em> release profiles indicated the diffusion process of the drug from Ca@oleogels was playing a dominating role in caffeine release. Furthermore, sustained intravitreal delivery was evidenced by higher drug levels from 12 h until the end of the pharmacokinetic study (240 h) and a 3.2-fold reduction in C_max in Ca@oleogel dosed rabbits compared to their caffeine dosed counterparts. Superior therapeutic effects were obtained with Ca@oleogels in a laser-induced mouse choroidal neovascularization model. Advantages of Ca@oleogels as caffeine delivery vehicles included excellent biocompatibility, low cost and simplicity of manufacturing as well, which indicated they can be administrated safely and were readily amenable to scale-up production cost-effectively. Moreover, sustained release of another hydrophilic model drug (congo red) was also demonstrated with the same formulation design. Therefore, this strategy serves as a general solution to sustained intravitreal delivery of hydrophilic small molecule drugs.</div></div>","PeriodicalId":15450,"journal":{"name":"Journal of Controlled Release","volume":"380 ","pages":"Pages 490-502"},"PeriodicalIF":10.5,"publicationDate":"2025-02-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143255743","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":"The strategy used by naïve anti-PEG antibodies to capture flexible and featureless PEG chains","authors":"Yiwei Liu ,&nbsp;Takahiro Mori ,&nbsp;Yusei Ito ,&nbsp;Kimiko Kuroki ,&nbsp;Seiichiro Hayashi ,&nbsp;Daisuke Kohda ,&nbsp;Taro Shimizu ,&nbsp;Tatsuhiro Ishida ,&nbsp;Steve R. Roffler ,&nbsp;Mika K. Kaneko ,&nbsp;Yukinari Kato ,&nbsp;Takao Arimori ,&nbsp;Takamasa Teramoto ,&nbsp;Kazuhiro Takemura ,&nbsp;Kenta Ishibashi ,&nbsp;Yoshiki Katayama ,&nbsp;Katsumi Maenaka ,&nbsp;Yoshimitsu Kakuta ,&nbsp;Akio Kitao ,&nbsp;Takeshi Mori","doi":"10.1016/j.jconrel.2025.02.001","DOIUrl":"10.1016/j.jconrel.2025.02.001","url":null,"abstract":"<div><div>Polyethylene glycol (PEG) is widely used as a standard stealth polymer, although the induction of anti-PEG antibodies and consequent effects have drawn attention in recent years. To date, several anti-PEG antibodies induced by PEG-modified proteins via the T cell-dependent (TD) pathway, in which affinity maturation occurs, have been reported. In contrast, structures of the naïve anti-PEG antibodies before affinity maturation have not been described in the literature. Here, to understand the details of the naïve anti-PEG antibodies capturing PEG, we studied a naïve anti-PEG antibody induced by a PEG-modified liposome in the absence of affinity maturation via the T cell-independent (TI) pathway. The mutation levels, structures as well as in vitro and in silico binding properties of TI and TD anti-PEG antibodies were compared. The TI anti-PEG antibody showed no mutation and a low binding affinity toward PEG, meanwhile, it allowed PEG chain sliding and weak interaction with the terminal group. Furthermore, the naïve anti-PEG antibodies may obtain high affinities by forming tunnel structures via minimal mutations. This research provides new insights into polymer–antibody interactions, which can facilitate the development of novel stealth polymers that can avoid antibody induction.</div></div>","PeriodicalId":15450,"journal":{"name":"Journal of Controlled Release","volume":"380 ","pages":"Pages 396-403"},"PeriodicalIF":10.5,"publicationDate":"2025-02-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143374224","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}