Journal of Controlled Release最新文献

{"title":"Remote loading of an autoantigen in PLGA nanoparticles for the treatment of multiple sclerosis","authors":"Corrine Din, Jin Xu, Mark Vander Roest, Hannah Dobson, Karl F. Olsen, April Kim, Helen Ju, Anna Schwendeman, James J. Moon, Steven P. Schwendeman","doi":"10.1016/j.jconrel.2025.114298","DOIUrl":"https://doi.org/10.1016/j.jconrel.2025.114298","url":null,"abstract":"Autoimmune diseases like multiple sclerosis (MS) affect millions of people worldwide and have been growing in prevalence. Current therapeutic strategies either entirely suppress immune function or only offer modest efficacy. Research efforts have shifted focus more recently to antigen-specific therapies to promote immune tolerance and avoid compromising general immune function. Here, we show the application of a novel aqueous remote loading method using poly(lactic-<em>co</em>-glycolic acid) nanoparticles (PLGA NPs) to load myelin oligodendrocyte glycoprotein (MOG) peptide at high loading and encapsulation efficiency. MOG is a target of autoreactive T cells in MS. These NPs (750 ± 200 nm and − 16.7 ± 0.4 mV zeta potential) slowly and continuously released MOG peptide and decreased costimulatory molecule expression on dendritic cells in vitro. A single dose of MOG-PLGA NPs administered either SC or IV exerted strong efficacy in a murine experimental autoimmune encephalomyelitis (EAE) model of MS. Prophylactic treatment with MOG-PLGA NPs prevented disease progression, while therapeutic treatment with MOG-PLGA NPs effectively reversed the EAE symptoms. MOG-PLGA NPs also induced long term tolerance against EAE re-challenge. Mechanistically, a single injection of MOG-PLGA NPs induced a 2-fold increase in the frequency of MOG-specific CD4+ T regulatory cells (Tregs) and anergic T cells, compared with PBS or free MOG peptide control groups. Additionally, histopathological analysis demonstrated a positive correlation between % demyelination and EAE score. Hence, autoantigens, such as MOG peptide, can be remote loaded into PLGA NPs from an aqueous solution at high loading and EE for long-term controlled release.","PeriodicalId":15450,"journal":{"name":"Journal of Controlled Release","volume":"51 1","pages":""},"PeriodicalIF":10.8,"publicationDate":"2025-10-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145260709","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":"Encapsulated cells as an enzyme replacement therapy for metachromatic leukodystrophy","authors":"Emilie Audouard, Florine Chereau, Camille Lupiet, Charlotte Mansat, Lucie Roger, Pauline Libert, Elena-Gaia Banchi, Nicolas Khefif, Dominique Farabos, Antonin Lamaziere, Marie-Anne Colle, Marc Folcher, Caroline Sevin, Françoise Piguet","doi":"10.1016/j.jconrel.2025.114307","DOIUrl":"https://doi.org/10.1016/j.jconrel.2025.114307","url":null,"abstract":"Metachromatic leukodystrophy (MLD) is a lysosomal storage disorder caused by an inherited deficiency of arylsulfatase A (ARSA) and characterized by accumulation of sulfatides in both glial cells and neurons resulting in myelin degeneration in the central and peripheral nervous systems, neuronal degeneration and neuroinflammation. Currently, no effective treatment is available for patients once symptoms are already present. Libmeldy©, an Ex vivo gene therapy, is the gold standard for pre-symptomatic patients with late-infantile and early juvenile MLD, and early symptomatic patients with early-juvenile MLD. Here, we investigated an innovative approach to deliver the recombinant ARSA enzyme by encapsulated-cell therapy. A cell-based device is capable of continuously delivering human ARSA compared to weekly intrathecal delivery of recombinant ARSA, which is under clinical evaluation in a phase II-III clinical trial. Two constructs of genetically engineered cells have been tested to determine which one could target more efficiently the central nervous system. Importantly, a dose response evaluation has been done with 2 doses (cells number loaded) to evaluate the best therapeutic effect. MLD mice were implanted at 6 months of age once disease is well established. The device biocompatibility as well as the therapeutic efficacy have been evaluated 3 months after implantation. The device was well tolerated in animals. Moreover, we demonstrate a correction of sulfatide storage and significant improvement of neuroinflammation in the CNS of all treated mice. All these data establish a strong rational to propose cell-based device therapy in symptomatic MLD patients.","PeriodicalId":15450,"journal":{"name":"Journal of Controlled Release","volume":"122 1","pages":""},"PeriodicalIF":10.8,"publicationDate":"2025-10-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145260657","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":"Surface-engineered robust hybrid lipid nanocapsules: A next-generation nanoplatform for mRNA delivery","authors":"Sunil Kumar Yadava, Anuja Tripathi, Mridula Kabilan, Julie A. Champion, Marcus T. Cicerone","doi":"10.1016/j.jconrel.2025.114312","DOIUrl":"https://doi.org/10.1016/j.jconrel.2025.114312","url":null,"abstract":"Hybrid lipid nanocapsules (hLNCs) represent a promising platform for mRNA delivery with the added benefit of ambient-temperature stabilization. Conventional hLNCs use polyethyleneimine (PEI) to facilitate mRNA binding, cellular uptake, and endosomal escape. However, PEI's high charge density is associated with cytotoxicity, nonspecific protein binding, and innate immune activation, features that may limit utility in chronic or repeat-dose applications. To overcome these limitations, we engineered the hLNC surface with either L-histidine (hLNC-Hist) or short-chain polyethylene glycol (hLNC-PEG) to improve biocompatibility. Both modifications reduced serum protein binding and enhanced cytocompatibility. hLNC-Hist preserved mRNA transfection in vitro and improved in vivo expression compared to unmodified hLNCs. In contrast, hLNC-PEG significantly reduced transfection efficiency. Notably, hLNC-Hist did not induce IgM or IgG responses and suppressed circulating pro-inflammatory cytokines following systemic administration - features that stand in contrast to the acute immune activation and anti-PEG antibody formation commonly observed with lipid nanoparticles (LNPs). Although hLNC-Hist did not achieve quite the peak transfection efficiency as LNPs in some models, hLNC-Hist did not exhibit the immunogenicity and reactogenicity that can limit repeated LNP dosing. hLNC-Hist offers a compelling alternative with an improved safety-efficacy profile for chronic mRNA delivery. Importantly, hLNC-Hist retained the ability to stabilize mRNA under ambient and elevated temperatures when embedded in sugar glass, enabling potential cold-chain-free deployment. These findings position hLNC-Hist as an immunologically silent, biocompatible, and thermally stable mRNA delivery vehicle. Its suitability for repeated administration makes it particularly attractive for emerging mRNA therapies requiring chronic dosing, including cancer immunotherapy, protein replacement, and autoimmune modulation.","PeriodicalId":15450,"journal":{"name":"Journal of Controlled Release","volume":"37 1","pages":""},"PeriodicalIF":10.8,"publicationDate":"2025-10-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145260708","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":"Claudin 5-binding small molecule transiently opens the blood-brain barrier and safely enhances brain drug delivery","authors":"Saito Inoue, Keisuke Shirakura, Atsuya Shirono, Jumpei Taguchi, Yoshiki Ikeda, Satomi Tomita, Risa Funatsu, Kosuke Muraoka, Yosuke Hashimoto, Keisuke Tachibana, Nobumasa Hino, Takefumi Doi, Yui Ikemi, Kazuto Nunomura, Bangzhong Lin, Shinsaku Nakagawa, Kazutake Tsujikawa, Shota Tanaka, Masanori Obana, Yasushi Fujio, Yoshiaki Okada","doi":"10.1016/j.jconrel.2025.114314","DOIUrl":"https://doi.org/10.1016/j.jconrel.2025.114314","url":null,"abstract":"The blood–brain barrier (BBB) protects the brain from harmful substances, but it also limits drug delivery, hindering the treatment of brain diseases. Claudin 5, a tight junction protein in endothelial cells, plays a key role in maintaining the BBB integrity. Although modulation of Claudin 5 is a promising strategy for transiently opening the BBB, the currently available modulators often cause adverse effects due to strong or prolonged activity. Thus, we aimed to develop a moderate Claudin 5 modulator that enables safe and transient opening of the BBB. We identified a Claudin 5-binding small molecule (CL5B), capable of binding Claudin 5 via a high-throughput screening of 9600 compounds using a Claudin 5 antibody and proteoliposomes. CL5B increased endothelial permeability and tracer permeation across the endothelial monolayer by altering the localization of Claudin 5 without affecting its expression. In mice, CL5B transiently opened the BBB for less than 30 min, delivering drugs specifically to the brain. Notably, CL5B-facilitated delivery of methylscopolamine, a drug with limited brain penetration, alleviated seizure symptoms in a mouse epilepsy model. These findings demonstrate that CL5B is a safe BBB modulator that enhances brain drug delivery and holds therapeutic potential for brain diseases.","PeriodicalId":15450,"journal":{"name":"Journal of Controlled Release","volume":"87 1","pages":""},"PeriodicalIF":10.8,"publicationDate":"2025-10-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145260710","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":"Transdermal hydrogen therapy for psoriasis using cavity-embedded double-conical microneedles","authors":"Dan Dan Zhu, Ryan Yi Da Lim, Yu Lin Poh, Dong Sheng Li, Srikala Raghavan, Peng Chen","doi":"10.1016/j.jconrel.2025.114313","DOIUrl":"https://doi.org/10.1016/j.jconrel.2025.114313","url":null,"abstract":"Psoriasis remains clinically incurable due to its complex etiology. Topical immunosuppressive therapies offer limited effectiveness partly because of poor skin permeability, and can cause severe side effects. To address these challenges, we developed a novel transdermal hydrogen therapy that targets the mutually-reinforcing coupling between oxidative stress and inflammation in psoriasis. Specifically, we designed a double-conical microneedle with high loading capacity and effective skin penetration to efficiently deliver MgH₂ powders, enabling the sustained release of molecular hydrogen within the skin tissue. This minimally invasive, self-administrable treatment significantly outperformed calcipotriol cream, a current standard topical therapy. The transdermal hydrogen therapy greatly relieved oxidative damages, pro-inflammatory cytokine expression, immune cell infiltration, and ultimately mitigated keratinocyte hyperproliferation and systemic symptoms. Furthermore, the mechanistic investigations provide valuable insights into psoriasis pathogenesis. More broadly, this study demonstrates a new solution for treating inflammatory skin diseases and a new strategy for microneedle-based transdermal therapeutic delivery.","PeriodicalId":15450,"journal":{"name":"Journal of Controlled Release","volume":"38 1","pages":""},"PeriodicalIF":10.8,"publicationDate":"2025-10-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145261354","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":"Balancing oral sequential absorption barriers of semaglutide-loaded nanoparticles by optimization of surface glycocholic acid density","authors":"Han Zeng, Yiyao Li, Boyuan Liu, Chenxiao Chu, Yupeng Feng, Peifu Xiao, Haoyang Yuan, Xiaopeng Deng, Yu Zhang, Tian Yin, Haibing He, Jingxin Gou, Xing Tang","doi":"10.1016/j.jconrel.2025.114316","DOIUrl":"https://doi.org/10.1016/j.jconrel.2025.114316","url":null,"abstract":"Nanoparticles (NPs) modified with glycocholic acid (GCA) at surfaces are considered promising tools to overcome oral drug delivery barriers. However, question on the influence of surface GCA density over delivery efficiency arises due to ligand-induced changes in surface properties of NPs. To answer this question, we engineered GCA-modified nanoparticles (GCA NPs) with different surface densities, and their surface hydrophobicity, mucus penetration, cellular uptake, apparent permeability coefficient (P_app), intracellular trafficking behavior and oral bioavailability were compared. The results turned out that GCA NPs were found with increased surface hydrophobicity, which limited their transport across mucus layer. Nanoparticles with 50 % surface GCA density (50 % GCA NPs) demonstrated optimal performance. Compared to 100 %GCA NPs, 50 %GCA NPs exhibited an 83.28 % improvement in mucosal penetration capability, while a 250.67 % increase in cellular uptake was noticed when comparing with PEG NPs. Overall, the 50 % GCA NPs significantly enhanced trans-epithelial transport across Caco-2/E-12 co-cultured monolayers, achieving a P_app value of 3.30 × 10⁻⁶ cm/s, while the P_app values of 100 %GCA NPs and PEG NPs were 2.23 × 10⁻⁶ cm/s and 1.73 × 10⁻⁶ cm/s. <em>In vivo</em> studies confirmed their therapeutic potential: oral administration of semaglutide (SMG)-loaded 50 % GCA NPs increased systemic SMG bioavailability to 12.12 %, achieving sustained glycemic control in type 2 diabetic rats. The optimized formulation exhibited favorable safety profiles and prolonged pharmacological effects. This study establishes a critical equilibrium between enhanced mucosal penetration and ligand-receptor interaction, while mitigating intracellular retention issues associated with high-density GCA-functionalized nanoparticles. These findings indicate that attentions should be paid in ligand-associated surface property alterations, which could exert unexpected influence on the performance of NPs constructed for oral peptide drug delivery.","PeriodicalId":15450,"journal":{"name":"Journal of Controlled Release","volume":"102 6 1","pages":""},"PeriodicalIF":10.8,"publicationDate":"2025-10-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145261008","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":"Polyphosphocholination of liposomic vehicles extends blood circulation, enhances cellular uptake, and lowers immunogenicity relative to PEGylation","authors":"Monika Kluzek, Maryana Hamad, Weifeng Lin, Evgenia Mitsou, Ziv Porat, Yuri Kuznetsov, Yaara Oppenheimer-Shaanan, Jacob Klein","doi":"10.1016/j.jconrel.2025.114306","DOIUrl":"https://doi.org/10.1016/j.jconrel.2025.114306","url":null,"abstract":"Intravenous liposomal drug delivery holds great promise for pharmaceutical efficacy, but faces challenges such as rapid clearance and immune system degradation. PEG-based liposome surface functionalization (PEGylation), currently the gold-standard and most widely-used approach to address these issues, is prone to reduced cellular uptake and accelerated bloodstream clearance (ABC) effect upon repeated administration due to immune activation. We demonstrate a novel liposome surface functionalization using poly(2-methacryloyloxyethyl phosphorylcholine) (pMPC) that significantly overcomes these limitations while maintaining comparable colloidal stability. Such polyphosphocholinated liposomes exhibit tunable cellular uptake, and prolonged blood circulation times, both modulated by polymer length, alongside reduced immunogenicity (lower IgM antibody elicitation) and a diminished ABC effect compared to PEG-liposomes. These polymer-length-dependent properties offer flexibility in optimizing drug delivery systems, positioning pMPCylated liposomes as a compelling alternative to PEGylated formulations with clear advantages for liposomal drug delivery therapeutics.","PeriodicalId":15450,"journal":{"name":"Journal of Controlled Release","volume":"7 1","pages":""},"PeriodicalIF":10.8,"publicationDate":"2025-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145260712","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":"Engineered lesion-homing liposomes encapsulating Rosuvastatin enhance spinal cord injury repair by preventing the formation of foamy macrophages","authors":"Zhide Liu, Jinyun Zhao, Haicheng Wen, Yiming Qin, Lifu Zheng, Yi Sun, Rundong He, Aozhuo Zu, Tianding Wu, Liyuan Jiang, Hongbin Lu, Jianzhong Hu, Yong Cao, Chunyue Duan","doi":"10.1016/j.jconrel.2025.114308","DOIUrl":"https://doi.org/10.1016/j.jconrel.2025.114308","url":null,"abstract":"Following spinal cord injury (SCI), infiltrating macrophages excessively phagocytose myelin debris, subsequently transforming into foamy macrophages that significantly exacerbate secondary injury pathology. In this study, we developed cysteine-alanine-glutamine-lysine (CAQK) tetrapeptide-modified liposomes (Lip) encapsulating Rosuvastatin (designated as CAQK-Lip-R), specifically engineered for targeted delivery to SCI lesions, to systematically investigate both the therapeutic effects and molecular mechanisms underlying CAQK-Lip-R-mediated inhibition of foamy macrophage formation and promotion of functional recovery after spinal cord injury. The novel-designed CAQK-Lip-R demonstrated efficient accumulation at injury sites and exerted substantial neuroprotective effects, as evidenced by significantly promoted functional recovery in the injured spinal cord. Mechanistically, these therapeutic benefits were achieved through regulation of myelin lipid debris clearance and macrophage polarization conversion via enhanced autophagy initiation and progression, coupled with effective suppression of PI3K/Akt/mTOR signaling axis activity and concomitant augmentation of autophagic flux in macrophages. Our findings not only elucidate a previously unrecognized mechanism of CAQK-Lip-R action in preventing foamy macrophage formation within the injured spinal cord microenvironment, but also present an innovative therapeutic paradigm utilizing a lesion-homing nano-delivery system for SCI treatment.","PeriodicalId":15450,"journal":{"name":"Journal of Controlled Release","volume":"114 1","pages":""},"PeriodicalIF":10.8,"publicationDate":"2025-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145260713","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":"Smart biomaterials, gels, drug delivery and the giant","authors":"Sei Kwang Hahn, Patrick Stayton, Yu-Kyoung Oh","doi":"10.1016/j.jconrel.2025.114300","DOIUrl":"https://doi.org/10.1016/j.jconrel.2025.114300","url":null,"abstract":"&lt;h2&gt;Section snippets&lt;/h2&gt;&lt;section&gt;&lt;section&gt;&lt;h2&gt;Innovations in inflammation and cancer therapy&lt;/h2&gt;Hoffman's vision of biomaterials as active partners with biology is reflected in advances that address inflammation and cancer. Torchilin and co-workers reviewed neutrophil extracellular traps as targets for nanomaterial-based interventions, highlighting DNase I and related agents to dismantle pathogenic traps and recalibrate inflammation [1]. In cancer, Kwon examined macropinocytosis as an actionable uptake pathway, outlining nanoplatform designs that exploit tumor-associated endocytosis while&lt;/section&gt;&lt;/section&gt;&lt;section&gt;&lt;section&gt;&lt;h2&gt;Advancing biomaterials for vascularization and brain-targeted delivery&lt;/h2&gt;Hoffman often emphasized the need for biomaterials to harmonize with physiology, a theme that resonates in new strategies to promote tissue integration and overcome delivery barriers. Sefton's work with polyacrylate scaffolds demonstrated how engineered biomaterials can guide vascularization and improve implant performance, underscoring the principle of materials-directed healing [7]. Extending this philosophy to neurological disease, Yun reported advances in intranasal delivery with&lt;/section&gt;&lt;/section&gt;&lt;section&gt;&lt;section&gt;&lt;h2&gt;Smart and responsive biointerfaces&lt;/h2&gt;Hoffman's groundbreaking contributions to stimuli-responsive hydrogels continue to inspire biomaterials that interact dynamically with their environment. Nakayama's visible-light responsive coatings enabled on-demand release of intact cell sheets, reframing the cell-material interface as an active therapeutic tool rather than a passive support [9]. Kikuchi demonstrated how thermoresponsive core-corona particles can be tuned to regulate phagocytosis, directly linking nanoscale structure to&lt;/section&gt;&lt;/section&gt;&lt;section&gt;&lt;section&gt;&lt;h2&gt;Translational biomaterials&lt;/h2&gt;Hoffman believed that biomaterials should address real clinical needs, a principle reflected in recent advances across inflammation, regeneration, and oncology. Mao developed a long-acting anti-TNF-α injectable for ulcerative colitis [12]. Kim and Tae advanced wound repair using collagen-binding extracellular vesicles and antioxidant hydrogels [13,14]. Yang applied HPMA polymer conjugates to regulate apoptosis in colon cancer [15]. Similarly, Park and co-workers highlighted bioadhesives and&lt;/section&gt;&lt;/section&gt;&lt;section&gt;&lt;section&gt;&lt;h2&gt;Nucleotide-based therapeutics&lt;/h2&gt;Hoffman's pioneering emphasis on polymers and controlled release resonated strongly in the fast-emerging field of RNA therapeutics. Miyata and &lt;em&gt;co&lt;/em&gt;-workers introduced silica-coated polyion complexes that stabilized pulmonary mRNA and improved mucosal delivery by tuning silica-layer integrity [20], while Hahn demonstrated transdermal siVEGF delivery using hyaluronate-coated lipid nanoparticles to suppress angiogenesis in skin cancer [21]. Kataoka further defined structure–function relationships&lt;/section&gt;&lt;/section&gt;&lt;section&gt;&lt;section&gt;&lt;h2&gt;Allan Hoffman's scientific leader","PeriodicalId":15450,"journal":{"name":"Journal of Controlled Release","volume":"12 1","pages":""},"PeriodicalIF":10.8,"publicationDate":"2025-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145255284","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A ratiometric theranostic nanoplatform with acid-triggered drug release and glutathione-activated fluorescence turn-on","authors":"Ricardo David Flores-Cruz, Yeshenia Figueroa-DePaz, Maria Carmona Lobita, Luis Felipe Hernández-Ayala, Alejandra Pilar López-Pacheco, Emma Dijkstra, Lena Ruiz-Azuara, Hélder A. Santos","doi":"10.1016/j.jconrel.2025.114309","DOIUrl":"https://doi.org/10.1016/j.jconrel.2025.114309","url":null,"abstract":"Theragnostic nanomedicines that precisely coordinate drug delivery with imaging remain a significant challenge. Here, we report a novel nanoformulation that integrates acid-sensitive drug release with a glutathione (GSH)-activated fluorescence turn-on mechanism for targeted cancer therapy and real-time tracking. Our system is based on folic acid-functionalized zinc oxide quantum dots (QFZnO) loaded with a third-generation Casiopeina drug, IIIGCas, a copper-based coordination compound. Upon reaching the acidic tumor microenvironment, IIIGCas is released, subsequent intracellular GSH reduction converts the non-fluorescent Cu(II) complex into a highly fluorescent Cu(I) adduct, activating a distinct “turn-ON” signal. Computational studies reveal that this redox switch suppresses photoinduced electron transfer, restoring the emission of the drug's intrinsic curcumin-derived fluorophore and amplifying its fluorescence by sixfold. This mechanism creates a dual-emission system, enabling the simultaneous ratiometric tracking of nanocarrier (QFZnO) localization and drug activation. The nanoplatform demonstrated enhanced potency, showing statistically significant cytotoxicity in cervical and triple-negative breast cancer cell lines at far lower doses than free IIIGCas. In vivo, using zebrafish xenograft models, it achieved precise tumor targeting and a 90 % reduction in primary tumor area, while effectively illuminating secondary micrometastases. This work provides a generalizable blueprint for designing intelligent metal-complex delivery systems that optically report their own therapeutic activation in real-time.","PeriodicalId":15450,"journal":{"name":"Journal of Controlled Release","volume":"36 1","pages":""},"PeriodicalIF":10.8,"publicationDate":"2025-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145255328","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}