Chondroitin sulfate functionalized nanozymes inhibit the inflammation feedback loop for enhanced atherosclerosis therapy by regulating intercellular crosstalk

In the inflammatory microenvironment of atherosclerotic plaques, metabolic dysregulation of superoxide anion (O 2 − ) and hydrogen peroxide (H 2 O 2 ) leads to the activation of feedback mechanisms involving IL-1β, TNF-α, and MCP-1, which triggers inflammatory cascades between macrophages and vascular smooth muscle cells (VSMCs) in atherosclerosis (AS). To address this, a chondroitin sulfate (CS)-functionalized dual-targeted engineered nanozyme, CS-Lip/PB@Rap, was developed by encapsulating mesoporous Prussian blue nanoparticles (PBs) loaded with rapamycin (Rap) within CS-modified liposomes. CS functionalization endowed CS-Lip/PB@Rap with a specific targeting ability for CD44 receptors, thus enabling targeted delivery to inflammatory macrophages and VSMCs. Moreover, its enhanced multiple enzyme-like activities effectively modulated the imbalance of oxidative stress. The underlying mechanism of crosstalk regulation by these engineered nanozymes may inhibit the NF-κB pathway by restoring normal metabolism of O 2 − and H 2 O 2 , thereby blocking the TNF-α, IL-1β, and MCP-1 feedback loops between macrophages and VSMCs. This process reduced the production of inflammatory macrophages and inhibited the VSMC transformation from a contractile phenotype to a synthetic phenotype, preventing the formation of fibrous caps. Furthermore, the elimination of oxidative stress could decrease the production of oxygenized low-density lipoprotein (ox-LDL), which inhibited the formation of foam cells and alleviated the atherogenic progression.