Immunomodulatory strategies and targeted delivery systems in atherosclerosis therapy

INTRODUCTION: Atherosclerosis (AS) is a chronic inflammatory disease where lipid-lowering therapy alone leaves 30-40% residual cardiovascular risk, underscoring the need for immunomodulatory interventions. AREAS COVERED: This review synthesizes literature (1990-2024) on AS immunopathology and targeted nanomedicine. EXPERT OPINION: Key mechanisms include dysregulated macrophage polarization (M1/M2 imbalance), Th1/Treg dysfunction, NLRP3 inflammasome activation, and NETosis. Immunomodulatory strategies are shifting from broad immunosuppression toward subset-specific precision intervention - targeting mitochondrial fission (DRP1), ANGPTL3, or epigenetic regulators (SET7). Concurrently, nanodelivery systems have evolved from single-ligand targeting to smart, biomimetic platforms (e.g. VLA-4/VCAM-1 dual-targeting, ROS-responsive release) that enhance spatiotemporal precision. Emerging frontiers include immunometabolic crosstalk (cholesterol crystals activating cGAS-STING) and interventions disrupting immune cell communication (LNP-delivered NLRP3 siRNA, PAD4 inhibitors). Major challenges persist - suboptimal plaque penetration, hepatic nanocarrier accumulation, and risks of systemic immunosuppression. Future breakthroughs require dual-modal platforms integrating immunomodulation with metabolic reprogramming, and multi-omics-guided personalized systems that leverage spatial transcriptomics to tailor delivery to patient-specific inflammatory niches. Bridging the gap between mechanistic elegance and clinical efficacy demands humanized models and flexible trial designs.