Targeted delivery of rapamycin and inhibition of platelet adhesion with multifunctional peptide nanoparticles for atherosclerosis treatment

Abstract

There is increasing evidence supporting the unique benefits of targeted therapy in treating atherosclerotic disease. Given the complex nature of atherosclerosis development, we proposed a novel strategy for the efficient delivery of rapamycin (RAPA) by targeting both the exposed subendothelial collagen and oxidized low-density lipoprotein (oxLDL) present in plaques. In response, we developed multifunctional peptide (MP) nanoparticles for targeted drug delivery. The ability of MP nanoparticles to load RAPA and target collagen/oxLDL was investigated through molecular dynamics simulations and in vitro experiments. The efficacy of MP nanoparticles in atherosclerosis treatment was assessed via in vivo experiments on ApoE^−/− mice. Results indicate that MP nanoparticles have encapsulation and drug loading efficiencies for RAPA of 78.3 % and 43.9 %, respectively. By targeting collagen, MP nanoparticles create steric hindrance that inhibits 77.2 % of platelet adhesion. These nanoparticles can also target oxLDL, delivering RAPA into plaques and significantly reducing macrophage uptake of oxLDL. In vivo experiments showed that MP nanoparticles effectively targeted and accumulated in plaques. Treating mice with MP@RAPA nanoparticles for 10 weeks led to an 81.3 % reduction in the aortic vascular plaque area and decreased concentrations of MCP-1, hs-CRP, MMP-1, P-selectin, IL-1β, and IL-8 inflammatory factors, as well as the optical density of platelet-associated proteins (CD42, CD61, and PECAM-1). These results highlight the promising potential of MP nanoparticles for atherosclerotic disease treatment.