SR-A-Targeted Nanoplatform for Sequential Photothermal/Photodynamic Ablation of Activated Macrophages to Alleviate Atherosclerosis

Cardiovascular and cerebrovascular diseases induced by atherosclerosis (AS) have become the dominant cause of disability and mortality throughout the world. The typical early pathological process of AS involves the activation of inflammatory macrophages in the vulnerable plaque. In this work, we first employed chitosan-coated carbon nanocages (CS-CNCs) as nanocarriers to load Chlorin e6 (Ce6) and then linked dextran sulfate (DS) to the outermost layer by electrostatic adsorption to create a multifunctional therapeutic nanoplatform, CS-CNCs@Ce6/DS. The DS of the nanoplatform can recognize and bind to the type A scavenger receptor (SR-A), which is expressed only on the activated macrophages of the arterial plaque, so the proposed nanoplatform selectively targets these macrophages and accumulates there. Furthermore, DS can competitively inhibit cellular endocytosis of oxidized low-density lipoproteins via blocking of SR-A. The rapid photothermal conversion capability of CS-CNCs enables efficient therapeutic delivery during photothermal therapy (PTT). Interestingly, near-infrared-accelerated drug release induced by initial 808-nm laser irradiation was observed, thus enhancing the Ce6 concentration in the atherosclerotic plaque area and the efficiency of photodynamic therapy (PDT). Sequential photothermal/photodynamic ablation of the activated macrophages reduced pro-inflammatory cytokine secretion and alleviated the proliferation and migration of smooth muscle cells. These finally resulted in the stabilization and shrinkage of atherosclerotic plaques, further inhibiting the development and exacerbation of AS. Therefore, this work achieved a "1 + 1 greater than 2" effect by providing a novel approach to the treatment of atherosclerotic plaques, which is promising for the prevention of AS-related diseases.