Journal of Controlled Release最新文献

{"title":"Receptor-mediated transcytosis of nanobodies targeting the heparin-binding EGF-like growth factor in human blood-brain barrier models","authors":"Boning Qiu ,&nbsp;Sara Pompe ,&nbsp;Katerina T. Xenaki ,&nbsp;Alessia Di Maggio ,&nbsp;Clara Belinchón Moreno ,&nbsp;Paul M.P. van Bergen en Henegouwen ,&nbsp;Enrico Mastrobattista ,&nbsp;Sabrina Oliveira ,&nbsp;Massimiliano Caiazzo","doi":"10.1016/j.jconrel.2025.113852","DOIUrl":"10.1016/j.jconrel.2025.113852","url":null,"abstract":"<div><div>Transport of molecules into the brain is regulated by the blood-brain barrier (BBB). Receptor-mediated transcytosis (RMT) is a targeted vesicular transport mechanism of brain endothelial cells that can be employed to specifically transport large therapeutic molecules into the brain. ProHB-EGF is the transmembrane precursor of the heparin-binding EGF-like growth factor (HB-EGF) present on the intraluminal side of the brain endothelial cells. This molecule is characterized as an internalizing transport receptor with so far no discovery of endogenous ligands. In this study, we describe the selection and characterization of two nanobodies (named F12 and H7) with high binding affinity for proHB-EGF and their BBB transcytosis potential were tested <em>in vitro</em>. For the human BBB model, we found that a polarized co-culture environment was crucial for the expression and cell surface display of proHB-EGF. The ability of F12 and H7 to pass the BBB <em>via</em> RMT was demonstrated in both a primary human brain microvascular endothelial cell-based BBB model and a human induced pluripotent stem cell (hiPSC)-derived iBBB model. Our studies demonstrate that the proHB-EGF targeting Nbs are promising BBB shuttle molecules for delivery of therapeutic molecules into the brain.</div></div>","PeriodicalId":15450,"journal":{"name":"Journal of Controlled Release","volume":"383 ","pages":"Article 113852"},"PeriodicalIF":10.5,"publicationDate":"2025-05-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144083250","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":"Broadly active intranasal influenza vaccine with a nanocomplex particulate adjuvant targeting mast cells and toll-like receptor 9","authors":"Luis Ontiveros-Padilla ,&nbsp;Dylan A. Hendy ,&nbsp;Erik S. Pena ,&nbsp;Grace L. Williamson ,&nbsp;Connor T. Murphy ,&nbsp;Nicole R. Lukesh ,&nbsp;Kathleen A. Ashcraft ,&nbsp;Mathew A. Abraham ,&nbsp;Chelsea D. Landon ,&nbsp;Herman F. Staats ,&nbsp;Soman N. Abraham ,&nbsp;Michael Carlock ,&nbsp;Ted M. Ross ,&nbsp;Nikolai Petrovsky ,&nbsp;Mark T. Heise ,&nbsp;Eric M. Bachelder ,&nbsp;Kristy M. Ainslie","doi":"10.1016/j.jconrel.2025.113855","DOIUrl":"10.1016/j.jconrel.2025.113855","url":null,"abstract":"<div><div>Flumist is the only FDA-approved intranasal influenza vaccine. Although it has recently been approved for at-home use, it has significant limitations. These include reduced effectiveness in generating a protective immune response in patients with extensive influenza exposure, safety concerns due to its live attenuated virus formulation, and reduced efficacy due to viral drift/shift. To address this limitation, we have developed a nanocomplex comprised of a mast cell (MC) agonist and toll-like receptor 9 (TLR9) ligand to adjuvant a broadly acting influenza antigen. The newly reported MC agonist was identified by screening mastoparan-7 analogs for MC degranulation activity, which led to a more active peptide analog, MP12W. Positively charged MP12W spontaneously forms nanoparticulate complexes (NPs) with CpG 1826 that were then used to intranasally vaccinate mice with a computationally optimized broadly reactive antigen (COBRA) hemagglutinin (HA) protein. The NPs were further optimized by substituting CpG 1826 with CpG 55.2, a TLR-9 agonist identified by machine learning to be more active in humans. MP12W-CpG 1826 NPs showed an increased pro-inflammatory response and decreased cytotoxicity in vitro compared to M7 complexes, translating into a safer profile in a model of increased hypersensitivity, collaborative cross mice 027 (CC027). Intranasal vaccination with this complex and broadly reactive HA resulted in higher mucosal antibody concentration and increased cytokine production with antigen recall. These responses were enhanced with MP12W-CpG 55.2 NP vaccination. MP12W-CpG NPs provided similar protection in an influenza challenge model. This study demonstrates the potential of this novel intranasal nanocomplex for vaccination.</div></div>","PeriodicalId":15450,"journal":{"name":"Journal of Controlled Release","volume":"384 ","pages":"Article 113855"},"PeriodicalIF":10.5,"publicationDate":"2025-05-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144083251","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":"In situ therapeutic vaccines for leukemia by chemo-nanoadjuvant therapy","authors":"Peng Zhang ,&nbsp;Guanhong Cui ,&nbsp;Tanzhen Wang ,&nbsp;Xiaofei Zhao ,&nbsp;Xinyue Wang ,&nbsp;Ruonan Ye ,&nbsp;Tianhui Liu ,&nbsp;Yiran Zheng ,&nbsp;Zhiyuan Zhong","doi":"10.1016/j.jconrel.2025.113851","DOIUrl":"10.1016/j.jconrel.2025.113851","url":null,"abstract":"<div><div>Therapeutic vaccines introduce a potentially ultimate cure for cancers including leukemia. The personalized vaccines relying on neoantigens though exhibiting clinical benefits are afflicted by long and delicate manufacture procedure, high cost, and possibly incomplete coverage of heterogeneous tumor cells. Here, we report a facile strategy to generate potent <em>in situ</em> therapeutic vaccines, which effectively eliminate leukemia and induce long-term anti-leukemia immunity, by homoharringtonine-nano-dual-adjuvant (HHT-NDA) therapy. HHT effectively kills leukemia cells and generates abundant tumor antigens <em>via</em> inducing immunogenic cell death. NDAs cooperatively promote the maturation and antigen-presentation of dendritic cells by activating both nucleotide-binding oligomerization domain-containing protein 2 and toll-like receptor 9. The HHT-NDA treatment of murine MLL-AF9 acute myeloid leukemia model leads to 57–71 % complete regression and 100 % protection from rechallenge, in accordance with expansion of memory CD8⁺ T cells. This standard-of-care chemotherapy in tandem with nano-dual-adjuvant offers a novel strategy to generate <em>in situ</em> therapeutic vaccines for leukemia.</div></div>","PeriodicalId":15450,"journal":{"name":"Journal of Controlled Release","volume":"383 ","pages":"Article 113851"},"PeriodicalIF":10.5,"publicationDate":"2025-05-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144083223","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":"Lipopeptide-mediated delivery of CRISPR/Cas9 ribonucleoprotein complexes for gene editing and correction","authors":"Mert Öktem ,&nbsp;Thai Hoang Nguyen ,&nbsp;Esmeralda D.C. Bosman ,&nbsp;Marcel H.A.M. Fens ,&nbsp;Massimiliano Caiazzo ,&nbsp;Enrico Mastrobattista ,&nbsp;Zhiyong Lei ,&nbsp;Olivier G. de Jong","doi":"10.1016/j.jconrel.2025.113854","DOIUrl":"10.1016/j.jconrel.2025.113854","url":null,"abstract":"<div><div>CRISPR/Cas gene editing is a highly promising technology for the treatment and even potential cure of genetic diseases. One of the major challenges for its therapeutic use is finding safe and effective vehicles for intracellular delivery of the CRISPR/Cas9 ribonucleoprotein (RNP) complex. In this study, we tested and characterized a series of novel fatty acid-modified versions of a previously reported Cas9 RNP carrier, consisting of a complex of the cell-penetrating peptide (CPP) LAH5 with Cas9 RNP and homology-directed DNA repair templates. Comparative experiments demonstrated that RNP/peptide nanocomplexes showed various improvements depending on the type of fatty acid modification. These improvements included enhanced stability in serum, improved membrane disruption capability and increased transfection efficacy. Cas9 RNP/oleic acid LAH5 peptide nanocomplexes showed the overall best performance for both gene editing and correction. Moreover, Cas9 RNP/oleic acid LAH5 nanocomplexes significantly protected the Cas9 protein cargo from enzymatic protease digestion. In addition, in vivo testing demonstrated successful gene editing after intramuscular administration. Despite the inherent barriers of the tightly organized muscle tissues, we achieved approximately 10 % gene editing in the skeletal muscle tissues when targeting the CAG-tdTomato locus in the transgenic Ai9 Cre-LoxP reporter mouse strain and 7 % gene editing when targeting the <em>Ccr5</em> gene, without any observable short-term toxicity. In conclusion, the oleic acid-modified LAH5 peptide is an effective delivery platform for direct Cas9/RNP delivery, and holds great potential for the development of new CRISPR/Cas9-based therapeutic applications for the treatment of genetic diseases.</div></div>","PeriodicalId":15450,"journal":{"name":"Journal of Controlled Release","volume":"383 ","pages":"Article 113854"},"PeriodicalIF":10.5,"publicationDate":"2025-05-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144083227","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":"In vitro-in vivo relationship and microstructural insights into long-acting levonorgestrel intrauterine systems","authors":"Suraj Fanse ,&nbsp;Andrew Clark ,&nbsp;Quanying Bao ,&nbsp;Ashwin Abhang ,&nbsp;Kellen Maurus ,&nbsp;Yuan Zou ,&nbsp;Yan Wang ,&nbsp;Shawn Zhang ,&nbsp;Diane J. Burgess","doi":"10.1016/j.jconrel.2025.113858","DOIUrl":"10.1016/j.jconrel.2025.113858","url":null,"abstract":"<div><div>Despite the proven high contraceptive efficacy and safety of levonorgestrel intrauterine systems (LNG-IUSs), no generic versions are currently available in the US market. This is primarily due to the challenges in achieving qualitative and quantitative (Q1/Q2) similarity with the reference listed drug (RLD) stemming from structural and mechanistic complexities, as well as the ultra-long duration of action (up to 8 years) of IUSs. The extremely long-acting release duration makes it difficult to navigate formulation decisions with even a modicum of speed. The burden to demonstrate bioequivalence hinges on awaiting years of release testing. Additionally, variations in microstructural arrangement can affect key formulation characteristics, potentially affecting bioavailability and bioequivalence. To address these challenges, this study presents a comprehensive reverse engineering analysis of commercial LNG-IUSs (Mirena® and Liletta®), including polymer crosslinking and physicochemical and mechanical characterization using FTIR, ssNMR, DSC, TGA, and SEM-EDX. X-ray microscopy (XRM) and focused ion beam-scanning electron microscopy (FIB-SEM) with AI-based analytics were employed to study microstructural changes in unreleased and post <em>in vitro</em> release samples, comparing commercial and in-house IUS variants. Real-time <em>in vitro</em> release testing was conducted for over 7 years for Mirena® and the in-house IUS, and up to 4 years for Liletta®. Additionally, an accelerated release method was developed, enabling full drug release within 100 days. Post-release analysis included assessment of levonorgestrel distribution, particle size, porosity, and structural changes across IUS layers, with findings revealing compositional differences that impact release kinetics.</div><div>Notably, this study is the first to report an <em>in vitro-in vivo</em> relationship (IVIVR) for ultralong-acting IUSs, correlating <em>in vitro</em> drug release data with <em>in vivo</em> LNG release profiles in humans. The established IVIVR offers a predictive tool for assessing drug release behavior in clinical settings, potentially reducing the clinical burden and accelerating drug development timelines. The current research offers a roadmap for manufacturers to refine their formulation and manufacturing processes to match target attributes. It is anticipated that this research will enhance public access to these highly effective long-acting reversible contraceptives.</div></div>","PeriodicalId":15450,"journal":{"name":"Journal of Controlled Release","volume":"383 ","pages":"Article 113858"},"PeriodicalIF":10.5,"publicationDate":"2025-05-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144083218","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Microneedle-adapted PAMAM-BSH delivery facilitates spatiotemporal matching for melanoma boron neutron capture therapy","authors":"Qiuyang Liu ,&nbsp;Linwen Lv ,&nbsp;Hao Li ,&nbsp;Haojun Liang ,&nbsp;Fan Hu ,&nbsp;Wenxi Su ,&nbsp;Junhui Zhang ,&nbsp;Ranran Chen ,&nbsp;Ziteng Chen ,&nbsp;Zhijie Wang ,&nbsp;Ruyu Yan ,&nbsp;Jun Chen ,&nbsp;Yanan Chang ,&nbsp;Juan Li ,&nbsp;Hui Yuan ,&nbsp;Gengmei Xing ,&nbsp;Kui Chen","doi":"10.1016/j.jconrel.2025.113863","DOIUrl":"10.1016/j.jconrel.2025.113863","url":null,"abstract":"<div><div>Boron Neutron Capture Therapy (BNCT) is a binary radiotherapy based on the combination of ¹⁰B drugs and thermal neutrons. Coordinating ¹⁰B with neutron irradiation will optimize the efficacy of BNCT, but further improvements are still required. Here, we develop a delivery system incorporating microneedles (MNs) and a modified boron agent PAMAM-BSH, enabling precise spatiotemporal matching of ¹⁰B with neutron irradiation for melanoma BNCT. The PAMAM-BSH is a cationic polymer ¹⁰B agent with amphiphilicity, forming nanomicelles in an aqueous solution. It exhibits high boron content and demonstrates good uptake and retention capabilities in cancer cells. When administering PAMAM-BSH-loaded MNs to melanoma-bearing mice, the duration for which the ¹⁰B content in tumors exceeds 20 ppm can extend up to 2 h. Notably, the system facilitates the precise administration of ¹⁰B into tumor cells, achieving concentrations exceeding 35 ng 10⁻⁶ cells. These contribute to an excellent alignment of spatiotemporal matching of ¹⁰B with neutron irradiation in BNCT. Meanwhile, the T/N (tumor-to-normal tissue) and T/B (tumor-to-blood) ratios can reach 30 and 100, respectively, which are much higher than the clinical BPA (T/N is 1.1–2.9, T/B is 1.1–3.6). Utilizing the system ultimately demonstrated a significant enhancement in melanoma BNCT, along with improved safety.</div></div>","PeriodicalId":15450,"journal":{"name":"Journal of Controlled Release","volume":"384 ","pages":"Article 113863"},"PeriodicalIF":10.5,"publicationDate":"2025-05-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144067297","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":"Highly pure mRNA vaccine provides robust immunization against P. aeruginosa by minimizing type I interferon responses","authors":"Ken Kawaguchi ,&nbsp;Le Bui Thao Nguyen ,&nbsp;Mao Kinoshita ,&nbsp;Naoko Abe ,&nbsp;Makoto Oba ,&nbsp;Hiroshi Abe ,&nbsp;Kazuki Sudo ,&nbsp;Keita Inoue ,&nbsp;Satoshi Uchida ,&nbsp;Teiji Sawa","doi":"10.1016/j.jconrel.2025.113860","DOIUrl":"10.1016/j.jconrel.2025.113860","url":null,"abstract":"<div><div>Developing effective vaccines against bacteria is critical given the growing threat of antimicrobial resistance (AMR). In this study, we developed mRNA vaccines targeting <em>Pseudomonas aeruginosa (P. aeruginosa)</em>, a key AMR pathogen, using PureCap mRNA encapsulated in lipid nanoparticles (LNPs). The PureCap technology offers a facile method for removing immunostimulatory impurities from in vitro transcribed mRNA, such as uncapped RNA and double-stranded RNA (dsRNA). Following intramuscular vaccination of mice with mRNA encoding a model antigen, PureCap mRNA elicited antibody titers that were 26-fold higher than those induced by conventional ARCA-capped mRNA. Mechanistic analyses revealed that both uncapped RNA and dsRNA impurities in ARCA-capped mRNA were responsible for the reduced humoral immune responses. While PureCap mRNA enhanced protein expression efficiency and reduced pro-inflammatory responses compared to ARCA-capped mRNA, minimizing pro-inflammatory responses was particularly critical. When anti-interferon-α/β receptor antibodies were administered, antibody responses to ARCA-capped mRNA vaccination were restored to levels comparable to those achieved with PureCap mRNA vaccination, highlighting the negative impact of type I interferon responses on antibody responses following vaccination with ARCA-capped mRNA. In a vaccination targeting the PcrV protein of <em>P. aeruginosa</em>, PureCap mRNA, but not ARCA-capped mRNA, significantly prolonged the survival of mice following bacterial challenges, presumably due to enhanced antibody production. Furthermore, PureCap mRNA vaccination significantly reduced bacterial loads in the lungs and mitigated tissue damage, edema, and inflammatory responses. These findings underscore the potential of PureCap mRNA as a promising platform for bacterial vaccination, offering a valuable strategy to combat AMR.</div></div>","PeriodicalId":15450,"journal":{"name":"Journal of Controlled Release","volume":"383 ","pages":"Article 113860"},"PeriodicalIF":10.5,"publicationDate":"2025-05-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144067290","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":"Cannabidiol-loaded hydrogel contact lenses for on-demand pH regulation and enhanced corneal alkali burn repair","authors":"Hongyan Zhang ,&nbsp;Ling-Min Lan ,&nbsp;Han-Jian Hu ,&nbsp;Yu Chen ,&nbsp;Tian Hu ,&nbsp;Hao Cheng ,&nbsp;Xiaolong Hu ,&nbsp;Shipeng Tang ,&nbsp;Xiao-Ping Liao ,&nbsp;Gang-Biao Jiang","doi":"10.1016/j.jconrel.2025.113859","DOIUrl":"10.1016/j.jconrel.2025.113859","url":null,"abstract":"<div><div>Corneal alkali burn (CAB) poses a significant therapeutic challenge due to alkali infiltration, bacterial infection, inflammation, and angiogenesis, which collectively hinder recovery. The pH microenvironment after CAB is critical for the healing process, but there are few functional biomaterials for this purpose at present. Herein, we develop a multifunctional hydrogel contact lens (CL) with on-demand release of citric acid (CA) and cannabinoid (CBD), triggered by alkaline conditions, to regulate the microenvironment pH and enhance CAB repair. The CA-functionalized polyvinyl alcohol (PC) and quaternary ammonium chitosan (QCS) are used as hydrogel frameworks, with CBD incorporated as a functional component. The (CBD/QCS/PC, CBD/QPC) hydrogel CL is fabricated using a repeated freeze-thaw process to achieve an interpenetrating network structure. The findings suggest that the 1CBD/QPC hydrogel CL exhibit superior mechanical properties and biocompatibility (hemolysis rate &lt; 0.6 %, cell viability&gt;90 %). These properties enhance wearing comfort and reducing secondary inflammation. Notably, this hydrogel can release CA (52.23 ± 2.78 %) and CBD (59.24 ± 5.15 %) within 24 h under alkaline conditions to neutralize pH, significantly down-regulate the expression level of inflammatory factors and remove hydroxyl radicals. This mechanism fundamentally addressing the secondary damage of residual lye following CAB. Moreover, the hydrogel CL exhibit potent inhibitory effects on the colonization and growth of both <em>E. coli</em> and <em>S. aureus</em> by destroying bacterial membranes, with an inhibition rate &gt; 90 %. In vivo results show that hydrogel CL promote the repair of CAB through anti-inflammatory effects and angiogenesis inhibition. In conclusion, these results demonstrate the potential of this hydrogel CL for treating corneal alkaline burns, providing new insights into treatment of CAB.</div></div>","PeriodicalId":15450,"journal":{"name":"Journal of Controlled Release","volume":"383 ","pages":"Article 113859"},"PeriodicalIF":10.5,"publicationDate":"2025-05-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144067292","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 combinatorial siRNA and mRNA approach for obesity treatment using targeting lipid nanoparticles","authors":"William Stewart ,&nbsp;Bin Hu ,&nbsp;Fengqiao Li ,&nbsp;Jia Huang ,&nbsp;Zhixiang Liu ,&nbsp;Chenshuang Zhang ,&nbsp;Maoping Tang ,&nbsp;Xue-Qing Zhang ,&nbsp;Xiaoyang Xu","doi":"10.1016/j.jconrel.2025.113857","DOIUrl":"10.1016/j.jconrel.2025.113857","url":null,"abstract":"<div><div>Obesity, a widespread global health issue affecting millions, is characterized by excess fat deposition and metabolic dysfunction, significantly elevating the risk of comorbidities like type 2 diabetes, cardiovascular disease, and certain cancers, all of which contribute to rising rates of preventable morbidity and mortality. Current approaches to obesity, including lifestyle modifications, and pharmacotherapy, often face limitations such as poor long-term adherence, side effects, and insufficient targeting of the complex, multifactorial pathways underlying the disease. Herein we report a dual, RNA-mediated combinatorial approach using targeting lipid nanoparticles (LNP) for the treatment of obesity. LNPs were co-encapsulated with mRNA encoding Interleukin-27 (<em>mIL-27</em>) to coactivate PGC-1α, PPARα, and UCP-1, thereby promoting adipocyte differentiation and enhancing adaptive thermogenesis within adipocytes, and siRNA targeting Dipeptidyl peptidase-4 (<em>siDPP-4</em>) to silence the primary inhibitory enzyme of GLP-1, and GIP within the incretin system, effectively restoring glucose homeostasis. Following post translational silencing of DPP-4 and upregulation of IL-27 in a diet-induced obesity (DIO) mice model, increased expression of thermogenic biomarkers PGC-1α, PPARα, and UCP-1 was observed at the molecular, protein, and tissue level, and insulin sensitivity was restored. Importantly, this gene modulation led to a 21.1 % reduction of bodyweight after treatment in the DIO model. These findings demonstrate for the first time a dual RNA-mediated combinatorial approach, leveraging liver targeting LNP delivery with synergistic effects from incretin system regulation and induction of adipocyte differentiation and thermogenesis after codelivery of <em>siDPP-4</em> and <em>mIL-27</em>. This innovative strategy provides a promising alternate framework for addressing obesity and its associated metabolic dysfunction.</div></div>","PeriodicalId":15450,"journal":{"name":"Journal of Controlled Release","volume":"383 ","pages":"Article 113857"},"PeriodicalIF":10.5,"publicationDate":"2025-05-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144066512","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":"Focused ultrasound augments the delivery and penetration of model therapeutics into cerebral cavernous malformations","authors":"Delaney G. Fisher ,&nbsp;Matthew R. Hoch ,&nbsp;Catherine M. Gorick ,&nbsp;Claire Huchthausen ,&nbsp;Victoria R. Breza ,&nbsp;Khadijeh A. Sharifi ,&nbsp;Petr Tvrdik ,&nbsp;G. Wilson Miller ,&nbsp;Richard J. Price","doi":"10.1016/j.jconrel.2025.113861","DOIUrl":"10.1016/j.jconrel.2025.113861","url":null,"abstract":"<div><div>Cerebral cavernous malformations (CCMs) are vascular neoplasms in the brain that can cause debilitating symptoms. Current treatments pose significant risks to some patients, motivating the development of new nonsurgical options. We recently discovered that focused ultrasound-microbubble treatment (FUS) arrests CCM formation and growth. Here, we build on this discovery and assess the ability of FUS to deliver model therapeutics into CCMs. T1 mapping MRI was used with 1 kDa (MultiHance; MH) and 17 kDa (GadoSpin D; GDS) contrast agents to assess the FUS-mediated delivery and penetration of model small molecule drugs and biologics, respectively, into CCMs of Krit1 mutant mice. FUS elevated MH delivery rate in lesion cores (4.6-fold) and perilesional spaces (6.7-fold). For the model biologic (i.e. GDS), FUS was of greater relative benefit, resulting in 21.7-fold and 3.8-fold delivery increases to the intralesional and perilesional spaces, respectively. These findings indicate that FUS can serve as a powerful non-invasive platform for augmenting therapeutic delivery to CCM.</div></div>","PeriodicalId":15450,"journal":{"name":"Journal of Controlled Release","volume":"383 ","pages":"Article 113861"},"PeriodicalIF":10.5,"publicationDate":"2025-05-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144067295","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}