Biomimetic nanocomplexes loading with evolocumab and curcumin for synergistic anti-atherosclerosis therapy in ApoE-/- mice.

Atherosclerosis (AS), a leading contributor to global cardiovascular mortality, is primarily driven by the dual pathological processes of chronic persistent inflammation and dysregulated lipid metabolism. Current clinical interventions are predominantly limited to single-target approaches (e.g., lipid-lowering therapies), which are insufficient for simultaneously modulating the two pathophysiological mechanisms and inhibiting atherosclerotic progression. Recently, combination therapeutic strategies based on multi-target and multi-organ synergistic effects have gained increasing attention in AS treatment. In this study, we developed a dual-functional nanodelivery system co-encapsulating PCSK9 inhibitor of evolocumab and natural anti-inflammatory agent of curcumin, with surface modification using macrophage membranes (Møm) and hyaluronic acid (HA). This novel design not only confers immune evasion capability to the nanocomplex but also facilitates drug accumulation in atherosclerotic lesions and hepatic tissues, thereby enabling synchronous regulation of the inflammatory microenvironment and lipid metabolic homeostasis. In vivo studies demonstrated remarkable therapeutic efficacy of this nanoformulation on atherosclerosis by effectively reducing plaque area, enhancing plaque stability and markedly ameliorating hepatic lipid accumulation. Overall, the proposed strategy, which enables multi-target and multi-organ synergistic regulation of inflammatory responses and lipid metabolism disorder, provides a promising approach for the clinical management of atherosclerosis.