Cationic PPC liposomes with dual targeting modules for enhanced liver fibrosis therapy via the extracellular matrix...

Activation of hepatic stellate cells (HSCs) 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 collagenase I 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 resulting system embodies an innovative HSC-ECM dual-targeting strategy through the 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 exhibited 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 HSC targeting and collagenase I activity-enhanced fibrotic barrier penetration, resulting in a 2.1-fold increase in the silybin B release efficiency in 8-72 h post-injection and an 85% reduction in the 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.