S2P-modified PLGA bifunctional nanodrug: inhibiting vascular senescence and foam cell formation for atherosclerosis treatment

The progression of atherosclerosis (AS) is closely related to endothelial senescence and abnormal lipid metabolism in macrophages. Although metformin (Met) can exert vascular endothelial protective effects by inhibiting endothelial cell senescence, the drug exhibits limited capacity to regulate lipid metabolism. In contrast, evolocumab (Evol), a PCSK9-specific inhibitor, can lower LDL-C levels to reduce foam cell formation. This study takes pathological endothelial cells and macrophages as core targets. Leveraging the complementary between Met-mediated anti-endothelial senescence and Evol-regulated lipid metabolism, S2P peptide-modified PLGA nanocarriers (S-P@(Met + Evol) NPs) were constructed to achieve co-delivery of the two drugs, further enhancing the dual-targeting function of the nanomedicine. In vitro studies showed that S-P@(Met + Evol) NPs effectively reduced oxidative damage, inhibited vascular aging and enhanced macrophage cholesterol efflux. In vivo studies showed that this nanodrug significantly alleviated aging damage, lipid accumulation, and inflammatory responses, synergistically reduced plaque burden, enhanced plaque stability, and exhibited a good safety profile. In conclusion, this dual-cell targeted synergistic regulation strategy provides an effective approach for the treatment of AS. Mechanism Synergistic Innovation: Combined use of metformin and evolocumab precisely meets the complementary requirement of inhibiting endothelial cell senescence and reducing foam cell formation, multi-dimensional intervention in core pathological processes of atherosclerosis. Precise Dual-Targeted Delivery: S2P peptide-modified PLGA nanocarriers enable dual targeting to injured endothelial cells and macrophages, thereby enhancing drug enrichment at the lesion site. High efficacy and safety: S-P@(Met + Evol) NPs inhibit aging and enhance cholesterol efflux, significantly reducing plaque burden, improving plaque stability, and exhibiting a good safety profile. High efficacy and safety: S-P@(Met + Evol) NPs inhibit aging and enhance cholesterol efflux, significantly reducing plaque burden, improving plaque stability, and exhibiting a good safety profile.