Coronary atherosclerosis (CA) remains a leading cause of global mortality. Its progression is driven by complex immunometabolic dysregulation and marked spatial heterogeneity within atherosclerotic plaques, which together hinder the development of precise therapeutic interventions. This review proposes a nano-enabled closed-loop engineering framework for spatially precise intervention in CA. First, we systematically describe how multimodal omics technologies, including single-cell transcriptomics and spatial transcriptomics, can be leveraged to dissect plaque microenvironmental features and enable the precise identification of spatially specific therapeutic targets, such as NLR family pyrin domain-containing 3 (NLRP3) and triggering receptor expressed on myeloid cells 2 (TREM2). Building on this foundation, we focus on engineering design strategies for omics-guided nanomaterial-based intervention platforms, and comprehensively discuss stimulus-responsive nanodelivery systems (e.g., reactive oxygen species- and pH-sensitive carriers) combined with ligand modifications (e.g., intercellular adhesion molecule-1 (ICAM-1)/vascular cell adhesion molecule-1 (VCAM-1) targeting) to achieve site-specific delivery of drugs and nucleic acids to high-risk plaque regions. Furthermore, we highlight the synergistic role of three-dimensional (3D) printed biomimetic scaffolds within this framework, which provide mechanical support while enabling localized and sustained therapeutic release, thereby synergizing with nanocarriers to enhance treatment efficacy. Importantly, this review explores how artificial intelligence and digital twin technologies can integrate multi-omics data with patient-specific imaging information to guide the design of intervention platforms and the development of therapeutic strategies through predictive simulation and personalized optimization. By integrating nanotechnology, advanced manufacturing, and intelligent systems, this review delineates an engineering-driven pathway toward closed-loop, spatially adaptive, and precision intervention for CA.