De Novo siRNA nanoplatform with NIR-II imaging for treatment of carotid atherosclerotic plaques

•A novel NIR-II fluorescent nanoplatform, RPC70NPs, designed for both imaging and siEpsin1/2 delivery to carotid atherosclerotic plaques.•Enables real-time, non-invasive monitoring of biodistribution, plaque localization, and treatment response.•Demonstrates significant suppression of plaque growth and lipid content in vivo.•Promising for early diagnosis and image-guided therapy of atherosclerosis. Reducing foam cell formation and accumulation within plaques is a critical strategy for treating atherosclerosis. Although current lipid-lowering therapies have significantly improved the management of atherosclerosis, the risk of cardiovascular events remains. Thus, it is necessary to explore next-generation therapies to reduce foam cell formation, inflammation, and oxidative stress. To address these challenges, we present an innovative near-infrared II (NIR-II) fluorescent dye coupled with a lesion-targeting peptide, forming a molecular self-assembly nanoplatform for effective in vitro small interfering RNA (siRNA) delivery. This platform downregulates Epsin1/2, a family of ubiquitin-binding endocytic adaptors, upregulates the expressions of ABCG1 and LRP-1 proteins, and markedly reduces foam cell formation. Additionally, this system enables real-time tracking of plaque accumulation, therapeutic response, and efficacy through in vivo noninvasive NIR-II imaging. Systemic siRNA delivery significantly suppresses lipid accumulation, plaque size, and necrotic core area in the carotid plaque model of ApoE−/− mice. These results suggest that this multi-functional nanoplatform could become an effective tool for NIR-II image-guided siRNA delivery for personalized treatment of atherosclerosis.