Polypyridiniums with Inherent Autophagy‐Inducing Activity for Atherosclerosis Treatment by Intracellularly Co‐Delivering Two Antioxidant Enzymes

Atherosclerosis is a chronic inflammatory disease of the arterial intima and is becoming the leading cause of morbidity and mortality worldwide. There is considerable evidence that defective autophagy and overproduction of reactive oxygen species (ROS) are closely involved in the development and progression of atherosclerosis. Here, a polymer is developed with the inherent autophagy-inducing activity to treat atherosclerosis by co-delivering antioxidant enzymes. The lead material P5c screened from a library of polypyridiniums shows robust efficacy in cytosolic protein delivery, and efficiently delivers superoxide dismutase (SOD) and catalase (CAT) into macrophages to down-regulate intracellular ROS. Moreover, P5c activates autophagy in macrophages and sufficiently inhibits foam cell formation. The P5c nanoparticle loaded with both SOD and CAT is further coated with neutrophil membranes to treat atherosclerosis in an ApoE^-/- mice model. The treatment exhibits potent anti-atherosclerosis effect via activating autophagy, decreasing the infiltration of senescent cells in atherosclerotic plaques, regulating the M2 polarization of macrophages, and restoring the structure and function of splenic corpuscles. The polymer offers a multifaceted approach to combat atherosclerosis, addressing both cellular dysfunction and the need for targeted protein delivery within affected cells.