Cationic PPC liposomes with dual targeting modules through extracellular matrix barrier for enhanced liver fibrosis therapy

Hepatic stellate cells (HSCs) activation is a key driver of fibrogenesis, while perisinusoidal collagen Ⅰ deposition establishes biophysical barriers that impede therapeutic delivery. To address this challenge, we developed a cationic liposome nanomicelle system (LIP/RSC) based on a polyenyl phosphatidylcholine (PPC) matrix, functionalized with collagenaseⅠ and dual silybin B-retinoic acid (silybin-RA) moieties. In this design, retinoic acid (RA) was covalently conjugated to two distinct components: (i) silybin B to form a targeted therapeutic complex (silybin-RA), and (ii) DSPE-PEG2000-NH2 to construct a long-circulating carrier (RA-DSPE-PEG2000). The resultant system embodies an innovative HSCs-ECM dual-targeting strategy through integration of dual RA modification technology -combining silybin-B targeting modification with DSPE-PEG2000 long-circulation modification -and spatiotemporally controlled silybin B release. The LIP/RSC system demonstrated cell-selective drug release profiles, with a 4-fold greater release of silybin B in CCl4-activated HSCs (LX-2-CCl4) than in hepatocytes (WRL68), accompanied by collagen normalization.The system conferred dual pharmacodynamics: slow-release kinetics prolonged circulation time (≥ 72 h) while enabling receptor-mediated HSCs targeting, and collagenaseⅠ activity enhanced fibrotic barrier penetration, resulting in a 2.1fold increase in silybin B release efficiency in 8-72 h post-injection and an 85% reduction in total collagen content in fibrotic murine models. This study validates LIP/RSC as an integrated nanoplatform that synergizes matrix remodeling with targeted drug delivery, thereby demonstrating enhanced therapeutic efficacy against hepatic fibrosis.