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

作者：Qigu Yao, Beiduo Wang, Jiong Yu, Qiaoling Pan, Yingduo Yu, Xudong Feng, Wenyi Chen, Jinfeng Yang, Changyou Gao, Hongcui Cao · 发表于：Journal of Controlled Release · 年份：2024 · DOI：10.1016/j.jconrel.2024.08.006 · 被引用次数：22 · 研究领域：Liver Diseases and Immunity、Pediatric Hepatobiliary Diseases and Treatments、Liver Disease Diagnosis and Treatment

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 H 2 O 2 -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...