Replacing cholesterol in liposomes by an Astragaloside IV derivative prolongs the circulation time and improves drug delivery to the fibrotic heart.

Myocardial fibrosis (MF) is a terminal pathological process in various cardiovascular diseases, posing a serious threat to human health. Despite the acknowledged advantages of liposomes in drug delivery for the targeted anti-MF therapy, the adverse effects of cholesterol greatly hinder the application of conventional liposomes. In this study, we designed Astragaloside IV derivative LS102 replacing cholesterol to construct a novel liposome delivering ferulic acid (LS-Lipo), aiming for the precise management of MF. Compared with conventional liposomes (CL-Lipo), LS-Lipo displayed smaller particle size, stronger stability, higher biosafety and enhanced intracellular uptake. As expected, LS-Lipo achieved targeted action to the fibrotic hearts and showed longer in vivo retention time compared to CL-Lipo. This phenomenon might be attributed to the decreased adsorption of plasma immune proteins and complement proteins after LS102 embedding. Meanwhile, LS-Lipo alleviated isoproterenol-induced fibrosis and myocardial injury, mainly involving in relieving the endothelial-mesenchymal transition, reducing the expressions of inflammatory factors (IL-17, IL-1β, IL-6), and inhibiting excessive collagen deposition. Collectively, these findings preliminarily indicated that LS-Lipo, with the advantages of safety, simplicity and efficiency, might replace conventional liposomes for MF therapy, showing good potential for further clinical application and transformation.