Microenvironment responsive nanoplatform for targeted removal of cholesterol and reshaping inflammatory microenvironment in atherosclerotic plaques

The microenvironment of atherosclerotic plaques features abundant cholesterol crystals (CCs), reactive oxygen species (ROS), and pro-inflammatory M1 macrophages, leading to the progression and mortality of atherosclerotic cardiovascular disease (ASCVD). Targeted removal of CCs and scavenging of ROS are crucial for treatment of ASCVD. In this study, an intelligent nanoformulation consisting of epigallocatechin gallate (EGCG), cysteine (Cys), ursodeoxycholic acid (UDCA) and VHPK (Valine-Histidine-Proline-Lysine)-Lipo, was designed to precisely target and remodel the inflammatory microenvironment of atherosclerotic plaques. With the assistance of VHPK peptide-modified liposomes, this nanoplatform significantly enhances the targeting ability and therapeutic efficacy. UDCA promotes cholesterol dissolution and efflux and improves cholesterol clearance in foam cells by over 70 %. EGCG, an antioxidant, significantly enhances ROS clearance by approximately 50 %. EGCG/Cys/UDCA@VHPK-Lipo boosts plaque clearance efficiency by 75.43 % in vivo . RNA-seq analysis reveals that these nanoparticles upregulate ATP-binding cassette transporters A1 ( ABCA1 ) and G1 ( ABCG1 ) expression, promoting cholesterol metabolism and M2 macrophage polarization. Additionally, inflammation markers in plasma and plaque tissues were significantly reduced, indicating good biocompatibility and safety. EGCG/Cys/UDCA@VHPK-Lipo demonstrates superior plaque clearance and safety both in vitro and in vivo , offering promising clinical potential for atherosclerosis treatment.