ROS-responsive nanoparticle delivery of obeticholic acid mitigate primary sclerosing cholangitis

• Published in: Journal of controlled release 2024-10, Vol.374, p.112-126
• Main Authors: Yao, Qigu, Wang, Beiduo, Yu, Jiong, Pan, Qiaoling, Yu, Yingduo, Feng, Xudong, Chen, Wenyi, Yang, Jinfeng, Gao, Changyou, Cao, Hongcui
• Format: Article
• Language: English
• Subjects: Animals; Apoptosis - drug effects; Chenodeoxycholic Acid - administration & dosage; Chenodeoxycholic Acid - analogs & derivatives; Chenodeoxycholic Acid - therapeutic use; Cholangitis, Sclerosing - drug therapy; Female; Humans; Male; Mesenchymal stem cell; Mesenchymal Stem Cells - drug effects; Mice; Mice, Inbred C57BL; Mitochondria; Nanoparticle Drug Delivery System; Nanoparticles - administration & dosage; Organoid; Placenta - drug effects; Placenta - metabolism; Pregnancy; Primary sclerosing cholangitis; Reactive Oxygen Species - metabolism; ROS-responsive nanoparticles
• ISSN: 0168-3659; 1873-4995; 1873-4995
• DOI: 10.1016/j.jconrel.2024.08.006

Primary sclerosing cholangitis (PSC) is a challenging cholestatic liver disease marked by progressive bile duct inflammation and fibrosis that has no FDA-approved therapy. Although obeticholic acid (OCA) has been sanctioned for PSC, its clinical utility in PSC is constrained by its potential hepatotoxicity. Here, we introduce a novel therapeutic construct consisting of OCA encapsulated within a reactive oxygen species (ROS)-responsive, biodegradable polymer, further cloaked with human placenta-derived mesenchymal stem cell (hP-MSC) membrane (MPPFTU@OCA). Using PSC patient-derived organoid models, we assessed its cellular uptake and cytotoxicity. Moreover, using a PSC mouse model induced by 3,5-diethoxycarbonyl-1,4-dihydro-collidine (DDC), we demonstrated that intravenous administration of MPPFTU@OCA not only improved cholestasis via the FXR-SHP pathway but also reduced macrophage infiltration and the accumulation of intracellular ROS, and alleviated mitochondria-induced apoptosis. Finally, we verified the ability of MPPFTU@OCA to inhibit mitochondrial ROS thereby alleviating apoptosis by measuring the mitochondrial adenosine triphosphate (ATP) concentration, ROS levels, and membrane potential (ΔΨm) using H2O2-stimulated PSC-derived organoids. These results illuminate the synergistic benefits of integrating an ROS-responsive biomimetic platform with OCA, offering a promising therapeutic avenue for PSC. ROS-responsive and self-positioning biomimetic nanoparticle delivery of obeticholic acid mitigates primary sclerosing cholangitis via mitochondria-induced apoptosis. [Display omitted] •ROS-responsive PPFTU material loaded with OCA alleviated hepatobiliary damage.•MSC membrane encapsulation enables powerful targeting of the liver and inflammation.•Organoids and animal models reveal that MPPFTU@OCA mitigates disease progression via mitochondrial-induced apoptosis.