A Multifunctional Polymeric Modulator Targeting Autophagic Lipid Efflux for Efficient Atherosclerosis Therapy

Impaired lipid metabolism and persistent accumulation of inflammatory macrophages represent major obstacles to effective anti-atherosclerotic (AS) therapy. To overcome the inherent limitations of conventional oral agents and nanocarrier-based systems, we developed a macrophage-targeted modulator by integrating curcumin (Cur) with gold nanoparticles (AuNPs). This construct was designed to concurrently correct dysregulated lipid homeostasis and suppress the expansion of pro-inflammatory macrophage populations. Specifically, protoporphyrin (Por) as a π-conjugated moiety was conjugated to polycaprolactone (PCL) via reactive oxygen species (ROS)-cleavable thioketal (TK) linkers, while AuNPs were functionalized onto hyaluronic acid (HA) backbones (HAPPT) to enable CD44-mediated foam cell recognition. Through self-assembly, Cur was efficiently loaded into the nano-system to yield the final modulator, Cur@HAPPT. Upon cellular uptake, Cur@HAPPT not only drove M1-to-M2 phenotypic repolarization but also provoked robust autophagic activation, collectively contributing to inflammation resolution. The autophagy-triggered cascade further facilitated lipid efflux and constrained inflammatory macrophage expansion, thereby producing a synergistic therapeutic benefit. Overall, Cur@HAPPT effectively attenuated AS progression and reinforced plaque stability, positioning this polymeric modulator as a promising targeted intervention for AS management.