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 (O2−) and hydrogen peroxide (H2O2) 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 O2− and H2O2, 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. Schematic diagram of the working principle of the engineered nanozyme CSLip/PB@Rap for atherosclerosis therapy. [Display omitted] •A dual-target engineered nanozyme delivery system, CS-Lip/PB@Rap, is constructed.•Engineered nanozymes block the inflammatory feedback loops between macrophages and VSMCs via inhibiting the NF-κB pathway.•Engineered nanozymes reduce the thickness of the fiber cap by inhibiting the production of synthetic phenotypic VSMCs.•Engineered nanozymes inhibit foam cell formation and lipid accumulation by reducing ox-LDL production.