Plaque‐Hepatic Targeting Nanotherapy Disrupts the PCSK9‐LOX‐1 Axis to Suppress oxLDL in Atherosclerosis

ABSTRACT Atherosclerosis remains the leading cause of cardiovascular mortality, with elevated oxidized low‐density lipoprotein (oxLDL) as a key driver. oxLDL metabolism involves two critical steps: generation mediated by proprotein convertase subtilisin/kexin type 9 (PCSK9)‐induced LDLR degradation, and plaque uptake via lectin‐like oxLDL receptor‐1 (LOX‐1). Current PCSK9 inhibitors reduce oxLDL production but show limited effects on plaque oxLDL uptake and inflammation. Thus, synergistic strategies targeting both steps are urgently needed. To address this, we developed a hepatic‐plaque targeting nanoparticle, siPCSK9@PEAL NPs‐aL, based on a PEG‐PLGA‐PLL framework. The nanoparticle was surface‐functionalized with anti‐LOX‐1 antibody for plaque targeting. Concurrently, optimized particle size enabled hepatic accumulation while minimizing clearance by the reticuloendothelial system (RES), facilitating effective hepatic delivery of siPCSK9. The PLGA core allowed controlled siRNA release, and the cationic PLL layer promoted efficient condensation and protection. In vitro, this system effectively silenced PCSK9, downregulated LOX‐1, rescued mitochondrial function and reduced apoptosis. In advanced atherosclerosis mice, weekly administration significantly reduced aortic plaque burden, stabilized plaque composition, and normalized serum lipid levels. Lipidomics showed oxLDL‐associated lipid downregulation and metabolic networks remodeling. Taken together, this dual‐targeting nanodrug integrates systemic lipid‐lowering with local anti‐inflammatory effects by simultaneously inhibiting oxLDL generation and utilization, offering a promising precision therapeutic strategy for atherosclerosis.