Journal of Controlled Release最新文献

{"title":"Nucleic acid-based nanogels with “offensive and defensive”effects for enhanced chemo-immunotherapy","authors":"Zijian Zhao ,&nbsp;Fei Sun ,&nbsp;Wenyu Wang ,&nbsp;Bing Li ,&nbsp;Yan Liang ,&nbsp;Dengshuai Wei ,&nbsp;Yong Sun ,&nbsp;Jianqin Yan","doi":"10.1016/j.jconrel.2025.113977","DOIUrl":"10.1016/j.jconrel.2025.113977","url":null,"abstract":"<div><div>Chemotherapeutic drugs such as doxorubicin (DOX) can activate CD8⁺ T cell-mediated antitumor immune responses by inducing immunogenic cell death (ICD), demonstrating the potential of chemo-immune synergistic therapy. However, the continuous stimulation of tumor antigens triggers the exhaustion of CD8⁺ T cells, which has become the main obstacle to inhibiting tumor growth and metastasis. Dual regulation of T cell infiltration and exhaustion to elicit a robust immune response is the key for optimizing tumor immunotherapy. In this study, a membrane-coated framework nucleic acid-based nanogel (RM@NG/DOX) was developed to co-deliver DOX and siRNA (siTOX, thymocyte selection-associated high mobility group box protein, TOX) for the spatiotemporal synergistic regulation of chemo-immunotherapy. This system broke the traditional cationic carrier mode of siRNA delivery and constructed a double-layer barrier to further protect the loaded siTOX and DOX. RM@NG/DOX induced ICD by DOX as an “offensive” signal to enhance T cell infiltration, while siTOX as a “defensive module” reversed the differentiation of exhausted T cells (PD-1⁺ Tim-3⁺) by silencing TOX, a key regulator of T cell exhaustion. Experiments <em>in vitro</em> and <em>in vivo</em> confirmed that RM@NG/DOX reshaped the immune microenvironment through the dual pathway of “activation-reversal” to effectively inhibit tumor growth and metastasis, successfully transforming the “cold tumor” into an immune-infiltrated “hot tumor” and enhancing chemo-immunotherapy. In summary, the combined chemo-genetic nanomedicine based on nucleic acid nanogels provides a new strategy for chemo-immunotherapy and the regulation of T cell exhaustion.</div></div>","PeriodicalId":15450,"journal":{"name":"Journal of Controlled Release","volume":"385 ","pages":"Article 113977"},"PeriodicalIF":10.5,"publicationDate":"2025-06-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144334842","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":"Homotypic biomimetic nanotheranostics enhance locoregional Cherenkov radiation-induced photodynamic therapy and ferroptosis in early bone metastases","authors":"Rui Xue, Shuai Li, Fengyu Wang, Xiaojing Zou, Beibei Zhang, Chunshui Yu, Qiusong Chen, Jin Wu, Chunyang Sun","doi":"10.1016/j.jconrel.2025.113971","DOIUrl":"https://doi.org/10.1016/j.jconrel.2025.113971","url":null,"abstract":"Theranostics for deep-seated and multifocal bone metastases using conventional nanoparticulate strategies face significant challenges due to limited targeting and insufficient spatial controllability within the lesions. Here, we developed a sophisticated nanocarrier (MC@MH) camouflaged with the homologous prostate cancer cell membrane and ferritin-homing peptide (HKN₂₂). Following systemic injection, the biomimetic nanotheranostics preferentially accumulated in bone metastases through a homotypic targeting mechanism. The acidic/H₂O₂-rich microenvironment triggered the degradation of MnO₂ in MC@MH, leading to the release of Mn²⁺ ions that enhance magnetic resonance imaging (MRI) for bone metastases, particularly at early stages. The HKN₂₂ further promoted interactions between MC@MH and intracellular ferritin. Guided by MRI, the separately administrated radionuclide (⁶⁸Ga-PSMA-617) also actively navigated to metastatic tumors. Based on the Cherenkov radiation effect, it served as a light source in the lesions, precisely irradiating the photosensitizer (Chlorin e6) released from MC@MH. The cytotoxic ROS generated from Cherenkov radiation-induced PDT not only destroyed cancer cells but also destructed ferritin to initiate a cascade of ferroptosis. Overall, our strategy facilitated bone remodeling and repair while preserving bone homeostasis, offering a novel avenue for locoregional and precise theranostics against metastatic cancer <em>in vivo</em>.","PeriodicalId":15450,"journal":{"name":"Journal of Controlled Release","volume":"14 1","pages":""},"PeriodicalIF":10.8,"publicationDate":"2025-06-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144329177","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":"High-resolution imaging reveals a cascade of interconnected cellular bioeffects differentiating the long-term fates of sonoporated cells","authors":"Jonathan L.F. Lee, Jae Song, Rumelo Amor, Jonathon Bolton, Andrew Thompson, Jürgen Götz, Pranesh Padmanabhan","doi":"10.1016/j.jconrel.2025.113974","DOIUrl":"https://doi.org/10.1016/j.jconrel.2025.113974","url":null,"abstract":"Low-intensity ultrasound combined with microbubbles is a promising, non-invasive treatment strategy for enhancing vascular permeability and targeted intracellular drug or gene delivery. Following ultrasound insonification, cells can undergo reversible sonoporation, involving adaptation and recovery, or irreversible sonoporation, marked by a loss of cell viability. To design effective sonoporation-based therapeutic delivery strategies, it is therefore critical to identify the biological responses that determine these distinct cell fates. Here, we developed a custom-built high-resolution multicolour imaging device and applied a single pulse of ultrasound (267 kHz frequency, 20 μs duration, and ~ 110 kPa peak negative pressure) to trigger targeted microbubble-mediated reversible and irreversible sonoporation events within a confluent monolayer of cultured Madin-Darby canine kidney (MDCK) II cells. We found that intracellular calcium levels rose rapidly and peaked within 10 s in both types of sonoporated cells, although the levels declined differently. In reversibly sonoporated cells, these levels gradually returned to baseline, whereas in irreversibly sonoporated cells, they dropped rapidly, falling well below baseline within 7.9 ± 3.0 min (mean ± s.d.). Using single-vesicle imaging, we further found that vesicles containing the tight junction protein claudin-5 remained mobile with subtly reduced movement in reversibly sonoporated cells, whereas they almost stalled in irreversibly sonoporated cells. The underlying microtubule network was partially disrupted in the reversibly sonoporated cells, recovering fully within 3.2 ± 2.9 min (mean ± s.d.). In contrast, in irreversibly sonoporated cells, the entire microtubule network collapsed within 4.0 ± 2.4 min (mean ± s.d.). Whilst in reversibly sonoporated cells, the uptake of the model drug propidium iodide was mild-to-moderate, without drastic cell size changes up to about 1 h post-sonication, irreversibly sonoporated cells presented with substantially higher propidium iodide uptake and completely shrank within 43.2 ± 10.5 min (mean ± s.d.). Together, our study identified distinct spatiotemporal sequences of interconnected biological responses underlying the different fates of sonoporated cells, providing a framework for identifying processes that could be manipulated for safe and effective sonoporation-based drug delivery.","PeriodicalId":15450,"journal":{"name":"Journal of Controlled Release","volume":"22 1","pages":""},"PeriodicalIF":10.8,"publicationDate":"2025-06-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144334843","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":"Nano-golden adjuvant-polymersomes empower tumor photothermal-immunotherapy","authors":"Zhiwei Sun, Jingyi Wang, Beibei Guo, Songsong Zhao, Shiyu Miao, Mingyu Xia, Zhiyuan Zhong, Fenghua Meng","doi":"10.1016/j.jconrel.2025.113976","DOIUrl":"https://doi.org/10.1016/j.jconrel.2025.113976","url":null,"abstract":"The integration of photothermal therapy with immunotherapy represent a potential treatment for tumor patients. Here, we demonstrate that nano‑golden adjuvant-polymersomes (nGAP) with gold nanoclusters imbedded in the membrane and immunoadjuvant poly(I:C) encapsulated within the aqueous core empower tumor photothermal-immunotherapy. Upon near-infrared irradiation, nGAP elicits a strong photothermal effect on tumor cells, driving immunogenic cell death and activating dendritic cells. In murine LLC lung tumor models, a single session of irradiation following intratumoral injection of nGAP led to an impressive 83 % cure rate, which further increased to 100 % complete regression by equipping cRGD peptide on the polymersome surface and combining with anti-CTLA-4 antibody. Furthermore, the cured mice exhibited effective resistance to subsequent tumor re-challenges. Our findings also reveal that nGAP yields explicit abscopal effects, supporting the development of systemic and long-lasting anticancer immunity. nGAP presents an interesting therapeutic modality capable of effectively ablating both primary solid tumors and their metastatic counterparts.","PeriodicalId":15450,"journal":{"name":"Journal of Controlled Release","volume":"7 1","pages":""},"PeriodicalIF":10.8,"publicationDate":"2025-06-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144334841","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":"Mitochondria-targeted NAD+/O2 co-delivery interpenetrating network hydrogel for respiratory chain restoration and osteoarthritis therapy","authors":"Xiaolong Shen, Jinquan Hu, Chen Wang, Haoyi Wang, Huajian Zhong, Zifan Zhang, Guoqing Wen, Lei Wang, Minjie Dong, Ye Tian","doi":"10.1016/j.jconrel.2025.113975","DOIUrl":"https://doi.org/10.1016/j.jconrel.2025.113975","url":null,"abstract":"Mitochondrial respiratory chain dysfunction-induced chondrocyte senescence is a key contributor to the progression of osteoarthritis (OA), yet effective strategies for restoring mitochondrial respiratory homeostasis remain elusive. Herein, we develop a charge-guided micro/nano interpenetrating network hydrogel that targets cartilage and delivers a mitochondria-directed MnO₂-based nanoparticles, in which the nanozyme catalyzes intracellular hydrogen peroxide to generate oxygen while releasing nicotinamide adenine dinucleotide (NAD⁺) precursor via particle degradation, thereby enabling synchronized electron donor and acceptor supply to fully reactivate the mitochondrial respiratory chain and alleviate chondrocyte senescence. Comprehensive evaluations reveal that this system enhances the activity of key antioxidant enzymes including superoxide dismutase, catalase, and glutathione peroxidase, elevates the intracellular nicotinamide adenine dinucleotide/nicotinamide adenine dinucleotide hydrogen (NAD⁺/NADH) ratio, and suppresses the secretion of senescence-associated secretory phenotype factors, thereby preserving cartilage matrix integrity. Collectively, these findings underscore the therapeutic potential of this dual-delivery platform to achieve full-length mitochondrial respiratory chain activation, offering a compelling strategy to mitigate chondrocyte senescence and impede OA progression.","PeriodicalId":15450,"journal":{"name":"Journal of Controlled Release","volume":"57 1","pages":""},"PeriodicalIF":10.8,"publicationDate":"2025-06-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144335059","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 bacterial extracellular vesicles for gastrointestinal diseases","authors":"Xinke Nie, Qiqiong Li, Ying He, Yushan Xu, Shanfeng Qiao, Xingdong Wang, Fan Meng, Junhua Xie, Shaoping Nie","doi":"10.1016/j.jconrel.2025.113972","DOIUrl":"https://doi.org/10.1016/j.jconrel.2025.113972","url":null,"abstract":"The gut microbiota, a complex microbial ecosystem within the gastrointestinal (GI) tract, plays a pivotal role in maintaining GI homeostasis. Dysbiosis of this community is increasingly implicated in the pathogenesis of diverse GI disorders. Bacterial extracellular vesicles (bEVs) secreted from gut microbes have emerged as an innovative therapeutic nanoplatform for GI diseases. Their unique advantages, including intrinsic biocompatibility, low immunogenicity, high drug-loading capacity, ease of customization and scalability make them a promising candidate for next-generation nanotherapies. In this review, we first discuss the biogenesis pathways, composition and internalization mechanisms of bEVs, with a particular focused on the bioactivities and mechanisms of natural bEVs in modulating gut health. Additionally, we highlight different bEVs engineering approaches to enhance bEVs functionality, stability, and disease-specific targeting, offering insights applicable to GI therapy and beyond. Despite the great potential of bEVs in various biomedical applications, challenges remain in developing standardized, scalable and reproducible bEVs production methods to facilitate clinical translation. Addressing these barriers is critical to unlocking the full therapeutic potential of bEVs in the GI disorders and other biomedical applications.","PeriodicalId":15450,"journal":{"name":"Journal of Controlled Release","volume":"52 1","pages":""},"PeriodicalIF":10.8,"publicationDate":"2025-06-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144319608","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":"Programmable chronogenetic gene circuits for self-regulated circadian delivery of biologic drugs","authors":"Amanda Cimino ,&nbsp;Fiona Pat ,&nbsp;Omolabake Oyebamiji ,&nbsp;Lara Pferdehirt ,&nbsp;Christine T.N. Pham ,&nbsp;Erik D. Herzog ,&nbsp;Farshid Guilak","doi":"10.1016/j.jconrel.2025.113959","DOIUrl":"10.1016/j.jconrel.2025.113959","url":null,"abstract":"<div><div>Cells of the body rely on the circadian clock to orchestrate daily changes in physiology that impact both homeostatic and pathological conditions, such as the inflammatory autoimmune disease rheumatoid arthritis (RA). In RA, high levels of proinflammatory cytokines peak early in the morning hours, reflected by daily changes in joint stiffness. Chronotherapy (or circadian medicine) seeks to delivery drugs at optimal times to maximize their efficacy. However, chronotherapy remains a largely unexplored approach for disease modifying, antirheumatic treatment, particularly for cell-based therapies. In this study, we developed autonomous chronogenetic gene circuits that produce the biologic drug interleukin-1 receptor antagonist (IL-1Ra) with desired phase and amplitude. We compared expression of IL-1Ra from circuits that contained different circadian promoter elements (E'-boxes, D-boxes, or RREs) and their ability to respond to inflammatory challenges in murine pre-differentiated induced pluripotent stem cells (PDiPSC) or engineered cartilage pellets. We confirmed that each circuit reliably peaked at a distinct circadian time over multiple days. Engineered cells generated significant amounts of IL-1Ra on a circadian basis, which protected them from circadian dysregulation and inflammatory damage. These programmable chronogenetic circuits have the potential to align with an individual's circadian rhythm for optimized, self-regulated daily drug delivery.</div></div>","PeriodicalId":15450,"journal":{"name":"Journal of Controlled Release","volume":"385 ","pages":"Article 113959"},"PeriodicalIF":10.5,"publicationDate":"2025-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144311847","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":"High-velocity delivery of biologics via the gastrointestinal tract by self-pressurized oral capsules","authors":"Joshua I. Palacios, Amy J. Wood-Yang, Nicholas Klavohn, Nick Friesenhahn, Nisha Raman, Nusaiba Baker, Grant Ashby, Mark R. Prausnitz","doi":"10.1016/j.jconrel.2025.113963","DOIUrl":"https://doi.org/10.1016/j.jconrel.2025.113963","url":null,"abstract":"Biologic drugs have transformed medicine, but are limited by their need for administration by injection. To enable oral delivery of biologics, we propose convective force as a physical method to overcome the barriers of the gastrointestinal tract (GIT). We designed oral capsules that self-pressurize in the GIT, mechanically fail at a specific pressure (100–170 kPa), and eject lyophilized drug with sufficient velocity to penetrate the mucosal barrier. This oral, self-pressurized aerosol (OSPRAE) was produced by a coated gelatin capsule filled with pressure-generating effervescent excipients (sodium bicarbonate, citric acid) and drug in a biodegradable polymer chamber (poly(lactic acid)). After initial optimization <em>in vitro</em>, OSPRAE allowed for insulin delivery to surgically exposed intestinal mucosa <em>in vivo</em> with similar pharmacokinetics and pharmacodynamics to subcutaneous injection in rats, despite lower bioavailability. Histological analysis showed only superficial damage to the intestinal epithelium that was highly localized to the microscopic area of impact. Future studies should administer OSPRAE orally to larger animals and, ultimately, to humans. The OSPRAE capsule offers a novel method to increase delivery of biologics across the intestinal mucosa using convective force, which contrasts with prior approaches involving chemical penetration enhancers and electromechanical devices.","PeriodicalId":15450,"journal":{"name":"Journal of Controlled Release","volume":"8 1","pages":""},"PeriodicalIF":10.8,"publicationDate":"2025-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144311793","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":"Local delivery of IL-12 mRNA and indoximod prodrug potentiates antitumor immunity by increasing T cell effector function","authors":"Heewon Park ,&nbsp;In Kang ,&nbsp;Susam Lee ,&nbsp;Minsa Park ,&nbsp;Seungcheol Kim ,&nbsp;Su Yeon Lim ,&nbsp;Hoyeon Nam ,&nbsp;Dohyun Yun ,&nbsp;Sejin Kim ,&nbsp;Yesol Kim ,&nbsp;Ji Hoon Jeong ,&nbsp;Kyuri Lee ,&nbsp;Heung Kyu Lee ,&nbsp;Yong-kyu Lee ,&nbsp;Yeu-Chun Kim","doi":"10.1016/j.jconrel.2025.113970","DOIUrl":"10.1016/j.jconrel.2025.113970","url":null,"abstract":"<div><div>The administration of recombinant cytokines, particularly interleukin-12 (IL-12), holds promising clinical potential for treating various cancers. Sustained intratumoral delivery of IL-12 can restore tumor resident CD8⁺ effector T cells and induce the priming of antitumor CD8⁺ effector T cells. However, these CD8⁺ T cell-dependent anticancer efficacy is usually transient and accompanies the activation of immune suppressive CD4⁺Foxp3⁺ T regulatory cells. The underlying mechanism of T regulatory cell activation in IL-12 therapy is the upregulation of IFNγ dependent indoleamine 2,3-dioxygenase (IDO) expression. Due to this negative feedback, the combinatorial use of drugs should be considered to enhance the efficacy of IL-12-mediated therapy. Herein, we designed a lipid nanoparticle (LNP) system which can successfully deliver an IDO inhibitor indoximod (IND) and IL-12 encoding mRNA. In order to increase the loading efficiency, the IND prodrug was synthesized by conjugating IND with cholesterol by ester linkage. Optimized IND prodrug encapsulating LNP successfully transfected tumor cells and macrophages, resulting in the secretion of IL-12 cytokine. With IL-12 transfection, macrophages upregulated T cell co-stimulation factor and released TNFα cytokine, indicating that the tumor microenvironment could be changed from cold tumor to hot tumor for immunotherapy. Also, by the elevated secretion of IL-12 cytokine, T cells release high levels of IFNγ, which is a central role in IL-12-mediated immunotherapy. This co-delivery system presents a promising strategy to overcome the limitations of single IL-12-mediated therapy by simultaneously promoting antitumor immune responses and inhibiting immunosuppressive mechanisms, thereby enhancing the overall efficacy of cancer immunotherapy.</div></div>","PeriodicalId":15450,"journal":{"name":"Journal of Controlled Release","volume":"385 ","pages":"Article 113970"},"PeriodicalIF":10.5,"publicationDate":"2025-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144319710","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":"Human Fc CH2 domain modifies cholix transcytosis pathway to facilitate efficient oral therapeutic protein delivery","authors":"Alistair Taverner ,&nbsp;Tom Hunter ,&nbsp;Julia Mackay ,&nbsp;Valentyna Varenko ,&nbsp;Kate Gridley ,&nbsp;Randall J. Mrsny","doi":"10.1016/j.jconrel.2025.113964","DOIUrl":"10.1016/j.jconrel.2025.113964","url":null,"abstract":"<div><div>The first domain of the cholix (Chx) exotoxin can rapidly cross small intestinal epithelium using a vesicular apical to basal (A → B) transcytosis mechanism that exploits interactions with specific host cell proteins. This non-toxic element of Chx can efficiently ferry a covalently attached therapeutic protein cargo that results in deposition of the carrier-cargo chimera within the lamina propria where it is retained due the presence of Chx receptors present on cells in this compartment. Systemic delivery of a cargo using this pathway requires separation from Chx at a late stage of epithelial A → B transcytosis. Here, we use a furin protease-specific cleavage sequence (FCS) to genetically conjoin a protein cargo, human growth hormone (hGH), to produce chimeras designed to separate a Chx-cargo chimera in a furin⁺ vesicular compartment in the basal region of intestinal epithelium cells to facilitate systemic hGH delivery. Our studies demonstrate that in response to the Chx carrier, there is a redistribution and augmentation of apical furin⁺ compartments where pre-mature carrier-cargo separation events would dramatically limit systemic hGH delivery using this FCS strategy. Apical application of soybean trypsin inhibitor blocked A → B transcytosis of the Chx-FCS-hGH chimera, likely by inhibiting early trafficking events associated with RME involving furin. We now show that combining the Chx carrier with the Fc domain C_H2 element of human IgG1 in a position-specific manner provides a mechanism to bypass the apical furin⁺ vesicular compartment to reach the basal furin⁺ vesicular compartment where FCS scission allows for efficient hGH release into systemic circulation. Colocalization of the C_H2-Chx carrier with the Fc receptor-like A protein in the apical region of enterocytes soon after RME demonstrates this deviation from the A → B transcytosis pathway normally accessed by Chx. Using a solution optimized for delivery to rat ileum we observed the amount of hGH reaching the systemic circulation to be ∼4 % of the material delivered using the C_H2-Chx carrier, demonstrating that oral delivery of a therapeutic protein can be achieved using targeted vesicular transcellular routing.</div></div><div><h3>One sentence summary</h3><div>Combining domain I of the <em>Vibrio cholerae</em> exotoxin protein cholix with the C_H2 element of the human IgG1 Fc domain results in a modification of the transcytosis pathway used by this toxin element that avoids the apical endosomal compartment of polarized intestinal epithelial cell where furin-like proteases can prematurely separate cholix-based chimera molecules.</div></div>","PeriodicalId":15450,"journal":{"name":"Journal of Controlled Release","volume":"385 ","pages":"Article 113964"},"PeriodicalIF":10.5,"publicationDate":"2025-06-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144311794","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}