Drug Delivery最新文献

{"title":"Cerium oxide nanoparticles: antioxidant properties in silicosis treatment and biomedical application prospects-a dialectical consideration.","authors":"Ge Ban, Yuanjie Chen, Ran Zhao, Yingbing Liang, Simo Chen, Jingjing Jia, Chaoke Li, Jinwen Sima, Dan Ding, Xiaona Wang, Zhengkai Zhu, Yumin Han","doi":"10.1080/10717544.2026.2634421","DOIUrl":"10.1080/10717544.2026.2634421","url":null,"abstract":"<p><p>Silicosis is a progressive fibrotic lung disease precipitated by chronic inhalation of crystalline silica. Uptake of silica particles by alveolar macrophages initiates a cascade of persistent inflammation and oxidative stress, in which reactive oxygen species (ROS) are key mediators of cellular injury and fibroproliferative remodeling. This review synthesizes the current knowledge of ROS species and signaling in silicosis and evaluates nanomaterial-based antioxidant strategies with an emphasis on cerium oxide nanoparticles (CeO₂NPs). We examine the mechanistic attributes of CeO₂NPs - including reversible Ce³⁺/Ce⁴⁺ redox cycling and enzyme-mimetic superoxide dismutase/catalase-like activities - that underpin ROS scavenging, and appraise their therapeutic potential, delivery considerations, and constraints. In parallel, we highlight opportunities and challenges associated with alternative platforms such as gold, silver, and iron-oxide nanoparticles for mitigating silica-induced oxidative injury. Among these modalities, unresolved issues include the standardization of characterization, dose‒response relationships, long-term biodistribution and clearance, immunotoxicity, interference with physiological redox signaling, and optimization of drug loading for combination therapies. Addressing these biosafety and payload questions through rigorous in vitro and in vivo studies will be essential to advance nanomaterial-enabled interventions for silicosis and related pulmonary diseases toward clinical translation.</p>","PeriodicalId":11679,"journal":{"name":"Drug Delivery","volume":"33 1","pages":"2634421"},"PeriodicalIF":8.0,"publicationDate":"2026-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12958391/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147343866","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Lipid nanoparticles with aptamers enable targeted mRNA delivery to CD4⁺ T cells.","authors":"Shrey Shah, Meenakshi Ranasinghe, John Decker, Keith Fraser, Ying Wang, Sarah Kinlaw, Morgan Barker, Sawan Patel, Adam Friedman, Sherwood Yao","doi":"10.1080/10717544.2026.2637266","DOIUrl":"10.1080/10717544.2026.2637266","url":null,"abstract":"<p><p><i>In vivo</i> genetic engineering of T cells could overcome the logistical, biological, and safety challenges of <i>ex vivo</i> modification, but effective and safe delivery systems remain limited by a lack of cellular specificity. Here, we developed aptamer-functionalized lipid nanoparticles (LNPs) for targeted mRNA delivery to CD4 + T cells, employing both a validated CD4-binding aptamer (Apt62) and novel aptamers generated using our proprietary transformer-based AI language model, AptaBLE. LNPs formulated with ionizable lipid SM102 or MC3 and conjugated with aptamers at controlled densities were physiochemically characterized and assessed for binding, <i>in vitro</i> transfection, <i>in vivo</i> biodistribution, and safety evaluation. Aptamer-functionalized LNPs demonstrated selective nanomolar binding to recombinant CD4, achieved enhanced transfection of CD4⁺ versus CD4^- T cells <i>in vitro</i>, and significantly enriched mRNA delivery to immune-rich tissues <i>in vivo</i>, achieving up to 70-fold spleen signal enhancement with SM102 formulations Compared to non-targeted controls, while maintaining suitable safety profiles. Overall, these findings demonstrate aptamer-functionalized LNPs, augmented by AI-guided aptamer design, as a tunable, non-immunogenic platform for <i>in vivo</i> T-cell engineering.</p>","PeriodicalId":11679,"journal":{"name":"Drug Delivery","volume":"33 1","pages":"2637266"},"PeriodicalIF":8.0,"publicationDate":"2026-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12951662/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147316753","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Preparation of a new fixed-combination carteolol-netarsudil ophthalmic solution via one-pot pH-adjusting solubilization strategy for glaucoma treatment.","authors":"Dian Jiao, Tao Wang, Tu Lu, Xiaohua Ran, Yanxin Li, Yanhua Liu, Chunyang Zhao, Tianhong Zhang, He-Nan Liu, Jin Sun, Xiaoli Ma, Qikun Jiang","doi":"10.1080/10717544.2026.2708376","DOIUrl":"10.1080/10717544.2026.2708376","url":null,"abstract":"<p><p>Currently, the commercial fixed-combination of two agents is facing several clinical challenges, including suboptimal intraocular pressure (IOP) reduction, which requires multiple daily administrations, compromised bioavailability due to rapid tear film clearance and nasolacrimal drainage, and preservative-induced ocular surface toxicity. To address these limitations, we intend to develop a novel preservative-free, long-acting fixed-combination formulation of carteolol hydrochloride and netarsudil dimesylate. This once-daily formulation demonstrates enhanced therapeutic potential through optimized physicochemical stability and extended ocular residence time in theory. However, commercialized netarsudil dimesylate is precipitated when the pH of the solution is above 5.4 or when carteolol hydrochloride is mixed with netarsudil dimesylate. Consequently, the preservative-free and long-acting fixed-combination carteolol-netarsudil containing hydroxypropyl methylcellulose (HPMC) as a thickener (FC-CN-TKN) was prepared in a pH about 5.0 solution using an extremely simple one-pot pH-adjusting solubilization strategy, achieving stable co-solubilization of both active pharmaceutical ingredients. The optimized FC-CN-TKN formulation demonstrated excellent physicochemical stability under refrigerated storage conditions. Additionally, FC-CN exerted no influence on the intraocular penetration of each active compound in the pharmacokinetic study, and HPMC-mediated viscosity enhancement significantly prolonged precorneal retention, further improving its residence time and bioavailability. Importantly, once daily, FC-CN-TKN exerted a potent IOP-lowering effect and protective effect on retinal ganglion cells. The innovative FC-CN-TKN was stable, safe, and effective, being a promising glaucoma therapy.</p>","PeriodicalId":11679,"journal":{"name":"Drug Delivery","volume":"33 1","pages":"2708376"},"PeriodicalIF":8.0,"publicationDate":"2026-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13479515/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148764656","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"An injectable hydrogel for localized sustained release of artesunate in postoperative fibrosis prevention after glaucoma filtration surgery.","authors":"Guangshuang Tan, Lusi Zhang, Tong Wu, Jingyuan Liu, Ying Wu, Manyi Xiao, Cong Wang, Zheng Pan, Shutong Wang, Chunrun Chen, Shanshan Zhu, Zewei Wang, Boyan Ma, Datong Xu, Liyang Shi, Bing Jiang","doi":"10.1080/10717544.2026.2686511","DOIUrl":"10.1080/10717544.2026.2686511","url":null,"abstract":"<p><p>Glaucoma filtration surgery (GFS) is the definitive treatment for reducing intraocular pressure in patients with refractory glaucoma. However, postoperative scarring of the filtration tract is a major cause of surgical failure. Although artesunate (ART) exhibits significant antifibrotic efficacy, its clinical application is severely limited by poor solubility and a short half-life. This study designed and developed a new injectable hydrogel cross-linked by collagen and four-armed polyethylene glycol <i>N</i>-hydroxysuccinimide encapsulating ART (C-P@ART) to overcome the limitations of ART in ocular antifibrotic therapy and extensively examined its underlying mechanisms. Stable three-dimensional network structure, excellent biocompatibility, and sustained drug release characteristics of C-P@ART were validated through FTIR, rheological analysis, endotoxin-testing, scanning electron microscope (SEM), and <i>in vitro</i> and <i>in vivo</i> release assays. In a TGF-β1-induced fibroblast fibrosis model, C-P@ART significantly inhibited <i>α</i>-SMA expression concentration-dependently and exerted antifibrotic effects through dual regulation of TGF-β1/SMAD and PI3K/Akt pathways. Subsequently, we evaluated its antifibrotic efficacy in the rabbit GFS model, where the C-P@ART treatment group exhibited a significant reduction in postoperative collagen deposition and <i>α</i>-SMA-positive expression compared to the control group. C-P@ART inhibited NF-κB pathway activation and reduced inflammatory cell infiltration. In conclusion, these findings demonstrated that C-P@ART synergistically mitigates fibrosis and inflammation through sustained ART release, providing an innovative therapeutic strategy to enhance GFS outcomes.</p>","PeriodicalId":11679,"journal":{"name":"Drug Delivery","volume":"33 1","pages":"2686511"},"PeriodicalIF":8.0,"publicationDate":"2026-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13435280/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148891010","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Oral delivery of recombinant <i>Lactococcus lactis</i> expressing an IL-23 inhibitor as a potential therapeutic strategy for experimental colitis.","authors":"Eliska Kopecna, Leona Raskova Kafkova, Petr Kosztyu, Kristyna Sloupenska, Katerina Zachova, Alica Cutkova, Jozef Skarda, Jana Vaculova, Milan Kuchar, Natalya Panova, Stephen Walimbwa, Tina Vida Plavec, Ales Berlec, Petr Maly, Milan Raska","doi":"10.1080/10717544.2026.2726654","DOIUrl":"10.1080/10717544.2026.2726654","url":null,"abstract":"<p><p>Interleukin 23 (IL-23) is a key mediator of immune-mediated intestinal inflammation and plays an important role in the pathogenesis of inflammatory bowel disease. Inhibition of IL-23 signaling has therefore been validated as a therapeutic target in IBD. Here, we tested small binding proteins of non-immunoglobulin origin targeting either the IL-23 cytokine p19 subunit or the IL-23 receptor subunit IL-23R, designated ILP and REX binders, respectively. ILP317 and REX115 variants of formerly identified protein collections were tested in murine experimental colitis. <i>Lactococcus lactis</i> bacteria engineered for ILP317 or REX115 expression were administered to experimental mice via yogurt-coated food pellets before and during dextran sulfate sodium (DSS) and trinitrobenzenesulfonic acid (TNBS)-induced colitis. To compare both protein blockers, ILP317 and REX115 binders were administered intraperitoneally as soluble recombinant proteins. General health status, colon macroscopic and histological changes, mucosal tissue cell infiltration, local and systemic inflammatory cytokines were analyzed. In DSS- and TNBS-induced colitis, intraperitoneal administration of soluble ILP317 or REX115 reduced disease severity, including disease activity index, colon shortening, and mucosal inflammatory cell infiltration. Oral administration of recombinant <i>L. lactis</i> expressing ILP317 also showed consistent protective effects, whereas oral <i>L. lactis</i> expressing REX115 produced less pronounced effects in several experimental settings. Overall, ILP317 appeared more effective than REX115 when delivered orally by recombinant <i>L. lactis</i>. Oral administration of non-colonizing <i>L. lactis</i> expressing an IL-23p19 inhibitor may represent a promising preclinical strategy for the development of novel, non-invasive approaches to modulate intestinal inflammation.</p>","PeriodicalId":11679,"journal":{"name":"Drug Delivery","volume":"33 1","pages":"2726654"},"PeriodicalIF":8.0,"publicationDate":"2026-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13644427/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149105997","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Microneedle-based drug delivery for inflammatory and immune-mediated ocular diseases: current applications and future perspectives.","authors":"Baoyue Mi, Feng Jin, Jingqing Mu, Xia Hua","doi":"10.1080/10717544.2026.2730728","DOIUrl":"10.1080/10717544.2026.2730728","url":null,"abstract":"<p><p>Inflammatory and immune-mediated ocular diseases encompass a spectrum of conditions that arise from dysregulated immune-inflammatory responses marked by a chronic clinical course, a propensity for relapse, and a tendency to cause significant ocular tissue damage, which can lead to profound impairment of visual function. Dysregulation of the balance between immune cell subpopulations is central to the pathogenesis of many of these diseases. At present, non-specific treatments such as glucocorticoids and immunosuppressants form the cornerstone of therapy for inflammatory and immune-mediated ocular diseases. However, these treatments often suffer from poor bioavailability and targeting, cumbersome or invasive administration methods, and are associated with side effects such as increased intraocular pressure (IOP), cataracts, or glaucoma with frequent administration. These limitations underscore the urgent need for alternative drug delivery methods. Microneedles have emerged as an innovative approach to ocular drug delivery, offering distinct advantages over traditional eye drops and intravitreal injections. They enhance drug penetration and targeting, provide sustained release, and may reduce unnecessary drug exposure, thus holding great promise for the treatment of inflammatory and immune-mediated ocular diseases. This review aims to shed light on the unique benefits and efficacy of microneedles as drug-delivery systems for inflammatory and immune-mediated ocular diseases, with particular attention to noninfectious uveitis, corneal inflammatory disorders, inflammation-associated corneal neovascularization, and allergic conjunctivitis. It also discusses ocular safety and toxicity, manufacturing and standardization, regulatory challenges, and future prospects of microneedle applications, providing a comprehensive overview of their potential for ocular drug delivery.</p>","PeriodicalId":11679,"journal":{"name":"Drug Delivery","volume":"33 1","pages":"2730728"},"PeriodicalIF":8.0,"publicationDate":"2026-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13686209/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149223543","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targeted delivery of mRNA to immune cells for <i>in vivo</i> cell therapy.","authors":"Danyang Wang, Yumin Li, Jinfeng Deng, Mengxin Li, Lin-Ping Wu","doi":"10.1080/10717544.2026.2716510","DOIUrl":"10.1080/10717544.2026.2716510","url":null,"abstract":"<p><p>Messenger RNA (mRNA) therapeutics have revolutionized biomedicine by enabling direct <i>in vivo</i> programming of immune cells. This strategy bypasses the complex manufacturing and high costs associated with <i>ex vivo</i> cell therapies. However, efficient and specific systemic delivery of mRNA to target immune cell subsets remains a major translational hurdle. This review systematically examines engineering strategies that address this challenge. We first outline the key biological barriers to mRNA delivery, such as serum instability, nonspecific biodistribution, cellular uptake heterogeneity, and inefficient endosomal escape. Next, we comprehensively review advances in lipid nanoparticle (LNP) engineering, including discovering novel lipids, modulating compositions, conjugating targeting ligands, and incorporating stimuli-responsive elements, to enable enhanced tropism toward specific immune cells. Representative applications in oncology, protein replacement, autoimmune disease, and tissue regeneration are highlighted. Finally, we address translational challenges in safety, scalable manufacturing, and regulatory issues. The integration of rational material design, high-throughput screening, artificial intelligence, and interdisciplinary collaboration will be essential to advance next-generation targeted <i>in vivo</i> mRNA cell therapies toward clinical translation.</p>","PeriodicalId":11679,"journal":{"name":"Drug Delivery","volume":"33 1","pages":"2716510"},"PeriodicalIF":8.0,"publicationDate":"2026-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13474526/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148720193","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Angiopep-2-decorated bacterial outer membrane vesicles penetrate the blood-brain barrier for glioblastoma chemo-immunotherapy.","authors":"Pir Tariq Shah, Zhangrong Lou, Xiaojing Zhu, Wenrui Jin, Chen Chen, Tao Hu, Peng Guo, Xuanzhu Zhao, Fan Li, Yin Xiaoliang, Zhenyong Wu, Chengjun Wu","doi":"10.1080/10717544.2026.2660007","DOIUrl":"10.1080/10717544.2026.2660007","url":null,"abstract":"<p><p>Glioblastoma (GBM) therapy remains one of the most formidable challenges in oncology because of the blood-brain barrier (BBB), immunosuppressive tumor microenvironment, and drug resistance. To overcome these challenges, we designed engineered angiopep-2-decorated bacterial outer membrane vesicles for targeted drug delivery across the BBB. Using a novel autotransporter-based (AIDA-I) genetic engineering approach, we developed a novel platform via straightforward genetic modification of <i>E. coli</i> with our designed pAIDA1-ANG plasmid to stably display Angiopep-2 on OMVs (OMV-^ANG) for targeted BBB penetration via LDL receptor-related protein 1 (LRP1) receptor-mediated transcytosis. Our <i>in vitro</i> BBB model and real-time <i>in vivo</i> imaging confirmed the BBB penetration and transcytosis of OMV-^ANG and doxorubicin-loaded OMV-^ANG, with accelerated brain accumulation within 2-4 h post-injection and sustained retention for 6 h. In orthotopic GBM models, systemic DOX-OMV-^ANG administration extended survival, induced potent tumor suppression via DOX-induced apoptosis and OMV-^ANG-mediated immunomodulation, and triggered sustained IFN-<i>γ</i> elevation with macrophage and CD8 + T-cell recruitment. This engineered OMV-^ANG platform shows promise in overcoming critical therapeutic barriers in glioblastoma and warrants further investigation as a versatile delivery system for diverse CNS therapeutics.</p>","PeriodicalId":11679,"journal":{"name":"Drug Delivery","volume":"33 1","pages":"2660007"},"PeriodicalIF":8.0,"publicationDate":"2026-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13094214/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147697203","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Phytotherapeutics self-microemulsifying systems in pellet dosage form for enhanced intestinal drug delivery: formulation, stability, and <i>in-vivo</i> performance.","authors":"Gabriela Koutná, Jan Kotouček, Jan Macků, Kateřina Kubová, Martina Urbanová, Larisa Janisová, Ivana Šeděnková, Jan Muselík, Jakub Vysloužil, Josef Mašek, Eliška Mašková, Miroslava Pavelková, David Vetchý, Jiří Brus","doi":"10.1080/10717544.2026.2702133","DOIUrl":"10.1080/10717544.2026.2702133","url":null,"abstract":"<p><p>Self-microemulsifying drug delivery systems (SMEDDS) containing volatile phytotherapeutics such as thymol (T), carvacrol (C), and eugenol (E) present significant formulation challenges, even when solidified. Their instability and interactions with coatings often hinder intestinal delivery. To address these limitations, we developed solid SMEDDS consisting of pellets (microcrystalline cellulose/magnesium aluminometasilicate/chitosan) and enteric capsules (CEC) for enhanced intestinal delivery. Based on solubility and pseudo-ternary phase diagrams, SMEDDS formulations (SES1-3) differing in component ratios (glycerol monooleate/caprylocaproyl macrogol-8 glycerides/diethylene glycol monoethyl ether) with 5% w/w of each drug were identified, demonstrating nano-scale droplet sizes (PDI <0.4) and showing no phase separation over 6 months. Thermodynamic stability and liquid-state NMR revealed particle size variations with preserved structural integrity. The lead formulation SES1 exhibited superior ex-vivo intestinal permeation (T-SES1). CECs filled with T-, C-, and E-loaded SES1 pellets, respectively, prepared via extrusion/spheronization, exhibited in-vitro gastro-resistant release, and achieved > 85% drug release within 120  min after a pH change to 6.8 during a one-year stability study (25 °C; 60% RH). FTIR-ATR analysis of the CEC internal surface confirmed the temperature-dependent restructuring of hypromellose and E sorption, a phenomenon not observed with C or T, which is likely attributable to physicochemical distinctions. Oral administration of CEC with T-SES1-pellets (0.5  mg/kg) in piglets demonstrated a delayed peak plasma concentration (C_max 11.67  ng/mL at 9 h) and sustained systemic exposure (AUC 119.8 ng·h/mL). These in-vivo findings substantiate the gastro-protective effect and enhanced intestinal absorption, positioning the pellet/CEC system as a promising strategy for the application of volatile phytotherapeutics in current pharmacotherapy.</p>","PeriodicalId":11679,"journal":{"name":"Drug Delivery","volume":"33 1","pages":"2702133"},"PeriodicalIF":8.0,"publicationDate":"2026-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13374766/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148445189","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Lysosome-directed targeted protein degradation technologies for overcoming cancer drug resistance: mechanisms, design principles, and therapeutic opportunities.","authors":"Huixin Mao, Ying Zhang, Mingqi Liu, Yao Yao, Yujie Peng, Xuwei Zhou, Hao Huang, Weidong Fei, Caihong Zheng, Yiqing Ye","doi":"10.1080/10717544.2026.2679844","DOIUrl":"10.1080/10717544.2026.2679844","url":null,"abstract":"<p><p>Targeted protein degradation (TPD) has emerged as a promising therapeutic strategy to address cancer drug resistance by enabling the selective and efficient degradation of disease-associated proteins through cellular mechanisms. Since 2020, lysosome-targeting chimeras (LYTACs) have gained attention for expanding targeted protein degradation to extracellular and membrane-associated disease-related proteins beyond the reach of proteolysis-targeting chimeras (PROTACs). In practice, LYTACs can overcome resistance by degrading instead of inhibiting them. This efficient and durable removal of resistance-associated drivers thereby suppresses compensatory signaling, restores drug sensitivity, and contributes to remodeling the tumor microenvironment. To facilitate the clinical translation of this emerging technology, this review systematically compares the mechanistic and functional advantages of LYTACs over PROTACs, summarizes key design principles, and categorizes major LYTAC modalities, including AbTACs, MoDE-As, and nano-LYTACs. We further discuss their <i>in vivo</i> pharmacological behaviors, with particular emphasis on stability, tumor selectivity, and degradation efficiency. Importantly, this article comprehensively highlights recent advances in the application of LYTACs for overcoming therapeutic resistance, including resistance to chemotherapy, targeted therapy, and immunotherapy. Finally, current translational bottlenecks, such as delivery efficiency, receptor heterogeneity, and pharmacokinetic limitations, are critically analyzed. Collectively, while still in its early stages of development, LYTAC-based lysosomal degradation represents a promising, paradigm-shifting strategy for targeting previously intractable mechanisms of cancer resistance.</p>","PeriodicalId":11679,"journal":{"name":"Drug Delivery","volume":"33 1","pages":"2679844"},"PeriodicalIF":8.0,"publicationDate":"2026-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13220583/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148041643","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}