Xinke Nie, Qiqiong Li, Ying He, Yushan Xu, Shanfeng Qiao, Xingdong Wang, Fan Meng, Junhua Xie, Shaoping Nie
{"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}
Amanda Cimino , Fiona Pat , Omolabake Oyebamiji , Lara Pferdehirt , Christine T.N. Pham , Erik D. Herzog , Farshid Guilak
{"title":"Programmable chronogenetic gene circuits for self-regulated circadian delivery of biologic drugs","authors":"Amanda Cimino , Fiona Pat , Omolabake Oyebamiji , Lara Pferdehirt , Christine T.N. Pham , Erik D. Herzog , 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}
Joshua I. Palacios, Amy J. Wood-Yang, Nicholas Klavohn, Nick Friesenhahn, Nisha Raman, Nusaiba Baker, Grant Ashby, Mark R. Prausnitz
{"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}
Heewon Park , In Kang , Susam Lee , Minsa Park , Seungcheol Kim , Su Yeon Lim , Hoyeon Nam , Dohyun Yun , Sejin Kim , Yesol Kim , Ji Hoon Jeong , Kyuri Lee , Heung Kyu Lee , Yong-kyu Lee , Yeu-Chun Kim
{"title":"Local delivery of IL-12 mRNA and indoximod prodrug potentiates antitumor immunity by increasing T cell effector function","authors":"Heewon Park , In Kang , Susam Lee , Minsa Park , Seungcheol Kim , Su Yeon Lim , Hoyeon Nam , Dohyun Yun , Sejin Kim , Yesol Kim , Ji Hoon Jeong , Kyuri Lee , Heung Kyu Lee , Yong-kyu Lee , 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<sup>+</sup> effector T cells and induce the priming of antitumor CD8<sup>+</sup> effector T cells. However, these CD8<sup>+</sup> T cell-dependent anticancer efficacy is usually transient and accompanies the activation of immune suppressive CD4<sup>+</sup>Foxp3<sup>+</sup> 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}
Alistair Taverner , Tom Hunter , Julia Mackay , Valentyna Varenko , Kate Gridley , Randall J. Mrsny
{"title":"Human Fc CH2 domain modifies cholix transcytosis pathway to facilitate efficient oral therapeutic protein delivery","authors":"Alistair Taverner , Tom Hunter , Julia Mackay , Valentyna Varenko , Kate Gridley , 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<sup>+</sup> 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<sup>+</sup> 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<sub>H</sub>2 element of human IgG1 in a position-specific manner provides a mechanism to bypass the apical furin<sup>+</sup> vesicular compartment to reach the basal furin<sup>+</sup> vesicular compartment where FCS scission allows for efficient hGH release into systemic circulation. Colocalization of the C<sub>H</sub>2-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<sub>H</sub>2-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<sub>H</sub>2 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}
Xuyang Liu, Xinze Teng, Jiahao Wang, Gaoshuo Zhang, Wen Guo, Wei Zhang, Qinfu Zhao, Cheng Hu, Li Sun, Yuling Mao
{"title":"Exosome-based mucosal therapeutic and diagnostic system: towards clinical translation","authors":"Xuyang Liu, Xinze Teng, Jiahao Wang, Gaoshuo Zhang, Wen Guo, Wei Zhang, Qinfu Zhao, Cheng Hu, Li Sun, Yuling Mao","doi":"10.1016/j.jconrel.2025.113966","DOIUrl":"https://doi.org/10.1016/j.jconrel.2025.113966","url":null,"abstract":"The mucosa, as the body's largest immune organ, is involved in various diseases such as ulcerative colitis, respiratory conditions, and tumors. Mucosal delivery offers favorable patient compliance, strong localized therapeutic effects, and the ability to treat a broad spectrum of diseases. However, the multilayered barrier structure of mucosal tissues often hinders effective drug delivery. Although current nanotechnologies have demonstrated some success in overcoming mucosal barriers, they still encounter challenges such as immunogenicity, low stability, high production costs, and difficulties in clinical translation. Extracellular vesicles(EVs), natural nanoscale lipid bilayer vesicles found in plants, animals, microorganisms, and body fluids, possess high biocompatibility, low immunogenicity, targeted delivery, and an excellent capacity to cross biological barriers. Exosomes, a subtype of EVs, are emerging as promising bio-nanotherapeutic tools capable of addressing limitations that conventional nanoparticles cannot. Their cargo of nucleic acids and proteins enables both therapeutic and diagnostic functions across various diseases. Exosomes can effectively traverse mucosal barriers—including gastrointestinal, nasal, and ocular mucosa—thereby offering a potential solution to mucosal delivery challenge. Moreover, exosomes derived from mucosal secretions may serve as biomarkers for diagnosing mucosa-associated diseases, providing a non-invasive and easily accessible alternative to blood samples. This review aims to elucidate the therapeutic roles and mechanisms of exosomes from different sources as drug carriers or therapeutic agents in diseases treated via transmucosal delivery. It also summarizes the diagnostic potential of mucosal secretion-associated exosomes. In conclusion, this paper underscores the importance of exosomes in mucosal delivery, discusses their current limitations and future promise, and provides new insights into their clinical applications.","PeriodicalId":15450,"journal":{"name":"Journal of Controlled Release","volume":"183 1","pages":""},"PeriodicalIF":10.8,"publicationDate":"2025-06-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144311838","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}
Shuailong Liang , Yixiao Pan , Jiahao Wang , Zichao Jiang , Tianliang Ma , Sijie Chen , Mingyu Chen , Yinlin Wu , Yi Leng , Yihe Hu , Long Wang
{"title":"Bone-targeting ZIF-8 based nanoparticles loaded with vancomycin for the treatment of MRSA-induced periprosthetic joint infection","authors":"Shuailong Liang , Yixiao Pan , Jiahao Wang , Zichao Jiang , Tianliang Ma , Sijie Chen , Mingyu Chen , Yinlin Wu , Yi Leng , Yihe Hu , Long Wang","doi":"10.1016/j.jconrel.2025.113965","DOIUrl":"10.1016/j.jconrel.2025.113965","url":null,"abstract":"<div><div>Periprosthetic joint infection (PJI) caused by <em>methicillin-resistant Staphylococcus aureus</em> (MRSA) has become a global healthcare burden owing to increased drug resistance. The effectiveness of traditional antimicrobial drugs in their treatments is becoming increasingly limited. The search for new drug delivery strategies may help to address this issue. In this study, we fabricated vancomycin (Van)-loaded and zoledronic acid (ZOL)-modified zeolitic imidazolate framework-8 (ZIF-8) nanoparticles (NPs), named VZZ-8 NPs, which could effectively treat MRSA-induced PJI. ZOL endowed VZZ-8 NPs with preferential bone-targeting capability, particularly accumulating at sites of elevated bone metabolism during injury/infection, thereby ensuring maximized therapeutic bioavailability <em>in vivo</em>. VZZ-8 NPs maintained ZIF-8-mimetic stability at physiological pH (7.4) yet rapidly degraded in acidic infection microenvironments (pH 5.0), enabling on-demand co-release of Zn<sup>2+</sup> and Van for synergistic antibacterial effects. Moreover, Zn<sup>2+</sup> released from VZZ-8 NPs disrupted bacterial membrane permeability, thereby potentiating Van antimicrobial activity and reducing the required therapeutic dosage of Van. <em>In vitro</em> studies demonstrated that VZZ-8 NPs effectively eradicated 93.84 ± 7.38 % of MRSA and inhibited biofilm formation by 95.36 ± 0.13 %. In a murine model of MRSA-induced PJI, VZZ-8 NPs displayed robust antibacterial efficacy while simultaneously suppressing local TNF-α and IL-6 expression and preventing infection-mediated osteolysis, demonstrating comprehensive therapeutic potential for PJI treatment. Consequently, the engineered VZZ-8 NPs developed in this study provide an effective therapeutic approach for MRSA-induced PJI through their dual capability of targeted delivery and pH-responsive drug release.</div></div>","PeriodicalId":15450,"journal":{"name":"Journal of Controlled Release","volume":"385 ","pages":"Article 113965"},"PeriodicalIF":10.5,"publicationDate":"2025-06-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144311843","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}
Shiyu Chen , Weimin Yin , Hui Zhi , Xiaoyou Zhang , Lulu An , Zichen Yang , Rongjie Li , Yanni Cai , Caoyi You , Yan Li , Yongyong Li , Haiqing Dong
{"title":"Nanomedicine-mediated macrophage polarization enhances the iron-depleting effect of desferrioxamine for breast cancer immunotherapy","authors":"Shiyu Chen , Weimin Yin , Hui Zhi , Xiaoyou Zhang , Lulu An , Zichen Yang , Rongjie Li , Yanni Cai , Caoyi You , Yan Li , Yongyong Li , Haiqing Dong","doi":"10.1016/j.jconrel.2025.113956","DOIUrl":"10.1016/j.jconrel.2025.113956","url":null,"abstract":"<div><div>Therapeutic strategies targeting iron metabolism to disturb the physiological functions of tumor cells have emerged as promising avenues in cancer treatment. Deferoxamine (DFOM) is an effective FDA-approved iron chelator that actively eliminates iron from cells, inducing iron-related dysfunction. However, its use is considerably limited by off-target toxicities and the innate metabolic compensatory capacity of tumor cells. To address these challenges, herein, we developed a facile manganese-doped calcium phosphate mineralized nanoparticle loaded with DFOM (termed BSA@MnCaP@DFOM). These nanoparticles polarized tumor-associated macrophages to M1 phenotype via activating Toll-like receptor 4 (TLR4) pathway, thereby cutting off their iron supply to tumor cells. This promoted the iron depletion effect of DFOM, reduced ferritin heavy chain 1 (FTH1) expression, disrupted iron metabolism, and efficiently induced mitochondrial dysfunction in the highly iron-dependent 4 T1 breast cancer cells. Consequently, the treatment triggered immunogenic cell death in tumor cells, eliciting a robust antitumor T cells immune response. Combined with mitigation of the immunosuppressive microenvironment, tumor suppression was achieved (72.5 % inhibition rate). In summary, our nanoparticles offer a promising strategy for iron metabolism disruption-mediated breast cancer immunotherapy.</div></div>","PeriodicalId":15450,"journal":{"name":"Journal of Controlled Release","volume":"384 ","pages":"Article 113956"},"PeriodicalIF":10.5,"publicationDate":"2025-06-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144293785","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":"Coordinated modulation of glucose metabolism and immunity via metal-drug nanovesicles for hepatocellular carcinoma therapy","authors":"Mengjie Kong, Liyan Qiu","doi":"10.1016/j.jconrel.2025.113957","DOIUrl":"10.1016/j.jconrel.2025.113957","url":null,"abstract":"<div><div>A highly immunosuppressive microenvironment, along with disordered glucose metabolism, promotes immune evasion and compromises the effectiveness of cancer immunotherapy. To address these challenges, we developed a multifunctional C-B-M-Mn nanovesicle platform to disrupt tumor metabolism and enhance antitumor immunity. This system encapsulated BAY-876 (a Glut1 inhibitor) and MSA-2 (a STING agonist) in the nanovesicle membrane and incorporated Mn<sup>2+</sup> through chelation with gallic acid-modified chitosan oligomers within the nanovesicle core. Under acidic tumor conditions, the surface potential of the nanovesicles shifted to positive charge, facilitating cellular uptake. Once internalized by tumor cells, C-B-M-Mn released its cargo in response to acidic pH and high esterase activity. BAY-876-mediated glycolysis inhibition increased reactive oxygen species (ROS) production and triggered the release of mitochondrial DNA, thereby priming the cGAS–STING signaling pathway. Mn<sup>2+</sup> enhanced cGAS sensitivity, while MSA-2 further activated STING, promoting dendritic cell (DC) maturation and CD8<sup>+</sup> T and natural killer (NK) cell recruitment. In addition, this metabolic blockade reduced PD-L1 expression levels and mitigated immune evasion. Additionally, Mn<sup>2+</sup> provided MRI contrast enhancement, enabling simultaneous imaging and treatment. Collectively, these findings highlight the C-B-M-Mn platform as a promising strategy for integrated glucose metabolic inhibition and immunotherapeutic intervention to improve hepatocellular carcinoma (HCC) treatment.</div></div>","PeriodicalId":15450,"journal":{"name":"Journal of Controlled Release","volume":"384 ","pages":"Article 113957"},"PeriodicalIF":10.5,"publicationDate":"2025-06-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144293784","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}
Huanhuan Li , Lalitkumar Vora , Yaocun Li , Anjali Kiran Pandya , Jiawen Wang , Yidan Luo , Abraham M. Abraham , Ester Ballana , Eva Riveira , Maria Nevot , Joseph Houghton , Helen O. McCarthy , Ryan F. Donnelly
{"title":"Transdermal delivery of enfuvirtide using dissolving microneedles integrated with novel insertion and removal indicator","authors":"Huanhuan Li , Lalitkumar Vora , Yaocun Li , Anjali Kiran Pandya , Jiawen Wang , Yidan Luo , Abraham M. Abraham , Ester Ballana , Eva Riveira , Maria Nevot , Joseph Houghton , Helen O. McCarthy , Ryan F. Donnelly","doi":"10.1016/j.jconrel.2025.113954","DOIUrl":"10.1016/j.jconrel.2025.113954","url":null,"abstract":"<div><div>Enfuvirtide, the first HIV fusion inhibitor, exhibits remarkable antiviral efficacy and a favourable safety profile compared with antiretroviral therapy alone. However, its clinical application is constrained by the necessity for subcutaneous administration and the high incidence of injection site reactions (ISRs) in 98 % of patients. This study seeks to overcome these limitations by developing dissolving microneedle array patches (DMAPs), offering a painless and efficient alternative for enfuvirtide delivery. Two bilayer DMAP designs featuring poly(vinyl pyrrolidone) (PVP) based-hydrophilic and poly(lactic acid) (PLA)-based hydrophobic baseplates were engineered, incorporating a novel PLA-silica baseplate as a colorimetric dissolution indicator for visual feedback on successful patch insertion and timely removal. The DMAPs with embedded indicators exhibited a rapid color change from yellow to green within 3 min of insertion into the rats' dorsal skin. This change was triggered by hydration of the dye crystal violet encapsulated in silica, as interstitial fluid migrated from the needle shafts to the baseplate. A subsequent transition to purple occurred within 2 h due to further dye hydration, indicating complete needle dissolution and successful delivery of enfuvirtide. <em>In vivo</em> studies on Sprague Dawley rats demonstrated that enfuvirtide achieved a C<sub>max</sub> of 1864 ± 480 ng/mL at 0.5 h with the PLA-silica DMAP, compared to 973 ± 200 ng/mL at 1 h with the PVP-baseplate DMAP. Both formulations exhibited biocompatibility and safety <em>in vivo</em>, with the PLA-silica DMAP supporting rapid drug release suitable for short-term applications, while the PVP-based DMAP offered potential for long-term use without irritation. These findings underscore DMAPs as a promising alternative to subcutaneous injection of enfuvirtide, capable of reducing ISRs and potentially enhancing patient adherence. Notably, this work introduced an innovative solution for prompt patch removal upon complete drug delivery, effectively addressing dosing inconsistencies and enabling individualised administration, which is crucial for ensuring the reliability and patient acceptability for widespread adoption of this technology.</div></div>","PeriodicalId":15450,"journal":{"name":"Journal of Controlled Release","volume":"385 ","pages":"Article 113954"},"PeriodicalIF":10.5,"publicationDate":"2025-06-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144305170","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}