Reprogramming the immune landscape in atherosclerotic plaques via inorganic nano-immunotherapy

Atherosclerosis is a chronic inflammatory disease driven by immune cell interactions within plaques. Nanotherapeutics targeting immune regulation within plaques offer promising potential for atherosclerosis treatment. However, most nanotherapies target single immune subsets and rarely examine cross-cell anti-atherosclerotic mechanisms in plaques. Here we developed a novel and biocompatible inorganic nanoparticle platform (VPNS@P) that efficiently accumulates in the immune microenvironment of atherosclerotic plaques, particularly in macrophages, monocytes and partly T/B cells, with minimal off-target uptake. Additionally, our findings indicate that the VPNS@P not only reduce plaque areas but also substantially improve plaque stability in atherosclerotic mice with no side effects. Importantly, we unraveled the mechanisms of VPNS@P nano-immunotherapy in atherosclerosis through scRNA-seq and experimental validation, demonstrating that it modulates four key immune cell populations within plaques to suppress inflammation and enhance immunity. VPNS@P also reshaped intercellular communication among immune cells within plaques, revealing new therapeutic targets and avenues for atherosclerosis. This study reveals an immune-modulating nanotherapy for atherosclerosis, highlighting its potential in treating inflammatory diseases.