Biomaterial-enabled spatiotemporal regulation of regulated cell death: A novel therapeutic paradigm across the continuum of cardiovascular pathological degeneration

Background Cardiovascular diseases (CVDs) constitute a continuous pathological spectrum defined by progressive vascular pathological degeneration, namely the cardiovascular pathological degeneration continuum (CVPD). Its core pathological processes cover endothelial dysfunction, atherosclerotic plaque progression, myocardial ischemia/reperfusion injury (MIRI), vascular remodeling, and post-stent restenosis. Despite substantial advances in pharmacological treatment and interventional diagnosis and therapy, current therapeutic strategies still suffer from poor targeting specificity, insufficient temporal regulatory capacity, and failure to cope with the dynamic multi-stage progression of CVPD. Regulated cell death (RCD), encompassing multiple subtypes such as apoptosis, pyroptosis, ferroptosis, and autophagy disorder, acts as a core pathological hub that runs through various cardiovascular lesions and links inflammatory responses, oxidative stress and tissue remodeling. Objective This review systematically summarizes the spatiotemporal distribution characteristics of RCD in CVPD, emphatically concludes emerging biomaterial-based intervention strategies, and proposes a novel paradigm of biomaterial-mediated spatiotemporal RCD regulation for CVPD treatment, so as to achieve precise modulation of the RCD signaling network. Meanwhile, this paper elaborates how functional biomaterials serve as programmable intervention platforms to implement multi-scale therapeutic effects ranging from molecular signal regulation to tissue-level repair and regeneration. Methods Relevant literature published from database inception to June 2026 was comprehensively retrieved from PubMed and Web of Science. The search keywords covered diseases (atherosclerosis, myocardial infarction, myocardial ischemia/reperfusion injury, aortic aneurysm/aortic dissection), biomaterials (nanoparticles, hydrogels, vascular stents, exosomes, extracellular vesicles), target cells (endothelial cells, macrophages, vascular smooth muscle cells, cardiomyocytes), and RCD pathways (apoptosis, pyroptosis, ferroptosis, autophagy, necroptosis). All studies regarding biomaterial-mediated RCD regulation in in vitro and in vivo cardiovascular models were included. The types of biomaterials, targeted delivery strategies and underlying molecular mechanisms were systematically analyzed. Results CVPD is driven by a dynamic and spatially heterogeneous RCD signaling network that evolves continuously with disease progression. In the early stage of atherosclerosis, endothelial cell death induces inflammatory activation and lipid infiltration. During plaque progression, macrophage dysfunction and vascular smooth muscle cells (VSMCs) phenotypic transformation aggravate inflammatory responses and extracellular matrix (ECM) remodeling. In the stages of myocardial infarction and MIRI, excessive reactive oxygen species (ROS) accumulation and metabolic collapse trigger cardiomyocyte death mediated by multiple RCD pathways. In the post-stent restenosis stage, persistent inflammation and defective efferocytosis lead to adverse vascular remodeling. Functional biomaterials (e.g., nanoparticles, hydrogels, modified stents, exosome delivery systems) realize spatiotemporally precise regulation of RCD via four core functional modules: (1) long-acting structural carrier systems for drug loading; (2) lesion-specific targeted enrichment systems; (3) microenvironment-responsive drug release mechanisms (ROS, pH, and enzyme responsiveness); and (4) catalytic or biomimetic active components with redox regulatory functions. Furthermore, biomaterial-exosome hybrid systems can further strengthen intercellular communication and achieve programmable regulation of cell fate under multiple RCD pathways. Biomaterial platforms can stage-specifically and precisely modulate the RCD network, restore vascular endothelial integrity, inhibit inflammatory macrophage activation, block pathological VSMCs remodeling, reduce cardiomyocyte loss, and facilitate the repair of damaged tissues. Conclusion Biomaterial-enabled spatiotemporally controllable RCD regulation establishes an integrated and programmable novel therapeutic paradigm for CVPD treatment. Integrating three core advantages including lesion targeting, microenvironment responsiveness and multi-pathway RCD modulation, this therapeutic system matches the continuous pathological progression of CVPD and compensates for the inherent limitations of traditional drugs and interventional therapies. The biomaterial-based therapeutic platforms can precisely regulate the spatiotemporal RCD disorder in CVPD, further alleviate inflammation, oxidative stress and metabolic disturbance, and provide a novel theoretical basis for the clinical treatment of CVDs.