Spatiotemporal precision interventions for cardiac repair and regenerative therapy

www.nature.com/emm REVIEW ARTICLE OPEN Spatiotemporal precision interventions for cardiac repair and regenerative therapy Mei Hua Ting 1,2,3,10, Huipeng Zhang4,10, Siyuan Liu1,2,3,10, Peng Wang1,2,3, Hongjun Li ✉ ✉ Junbo Ge 6,7,8,9 and Ning Zhang 1,2,3,6,7,8,9 4,5 ✉ , Wenbin Zhang 1,2,3 ✉ , © The Author(s) 2026 1234567890();,: Restoring cardiac function after myocardial infarction remains a major challenge, as current pharmacological and interventional therapies primarily mitigate symptoms and slow disease progression without addressing the irreversible loss of functional myocardium. Although a diverse range of biologically active agents has been developed to modulate inflammation, angiogenesis, fibrosis, and cardiomyocyte survival, their therapeutic impact is frequently limited by delivery strategies that fail to match the dynamic and heterogeneous nature of post-infarction healing. Advances in biomaterials, nanotechnology, and device engineering have enabled drug delivery systems capable of spatiotemporally programmed therapeutic engagement. By responding to injuryassociated cues, recreating key features of the myocardial microenvironment, and incorporating programmable release architectures, these systems coordinate localization, release kinetics, and duration of action with distinct phases and regions of cardiac repair. When combined with appropriate delivery interfaces, including nanocarriers, injectable depots, structured platforms, and biologically derived vehicles, spatiotemporal drug delivery transforms therapy from passive administration into an active determinant of biological outcome. This Review synthesizes recent mechanistic and engineering advances to frame spatiotemporal precision as a unifying principle for cardiac drug delivery. Aligning therapeutic action with the intrinsic biology of myocardial healing provides a rational pathway toward more effective, durable, and biologically informed strategies for cardiac repair and, where biology permits, regeneration. Experimental & Molecular Medicine; https://doi.org/10.1038/s12276-026-01704-4 INTRODUCTION Ischemic heart disease remains the leading cause of mortality worldwide, accounting for more than nine million deaths each year1. Despite substantial advances in pharmacological therapy and revascularization procedures that have substantially improved survival after myocardial infarction (MI), these interventions mainly alleviate symptoms and slow disease progression rather than restoring lost myocardial tissue. The permanent loss of cardiomyocytes following infarction triggers maladaptive remodeling processes that progressively impair ventricular function and ultimately lead to heart failure (HF). This challenge is further complicated by the limited regenerative capacity of the adult heart, in which endogenous repair responses are modest, transient, and quickly replaced by fibrotic scar formation2. Efforts to transition from symptomatic treatment toward myocardial repair have therefore driven the development of various therapeutic approaches aimed at modulating inflammation, promoting angiogenesis, limiting fibrosis, and preserving cardiac function3. These strategies include various therapeutic cargoes such as small molecules, proteins, nucleic acids, and cellbased or vesicle-based agents. Despite encouraging biological rationale and preclinical efficacy, many of these therapies share a common limitation: ineffective delivery to the injured myocardium. Rapid systemic clearance, off-target biodistribution, and poor localization to infarcted tissue continue to constrain therapeutic impact, making drug delivery a central bottleneck in cardiac repair and regeneration. Alongside this change in therapeutic goals, drug delivery systems (DDS) have become a key focus, leading to various approaches aimed at enhancing myocardial localization and retention. These strategies encompass different delivery modalities, administration routes, and therapeutic objectives (Fig. 1). Nanoparticles, injectable hydrogels, patches, microneedle arrays, and biologically driven carriers have all been explored as vehicles to improve cardiac targeting, whereas systemic, catheter-based, and local delivery routes offer differing balances between accessibility and spatial control4,5. These approaches have expanded the therapeutic toolkit, bridging the gap between 1 Department of Cardiology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China. 2Zhejiang Key Laboratory of Cardiovascular Intervention and Precision Medicine, Hangzhou, China. 3Engineering Research Center for Cardiovascular Innovative Devices of Zhejiang Province, Hangzhou, China. 4State Key Laboratory of Advanced Drug Delivery and Release Systems, Key Laboratory of Advanced Drug Delivery Systems of Zhejiang Province, Liangzhu Laboratory, School of Pharmacy, Zhejiang University, Hangzhou, China. 5Department of Hepatobiliary and Pancreatic Surgery, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China. 6 Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai, China. 7Shanghai Institute of Cardiovascular Diseases, Shanghai, China. 8State Key Laboratory of Cardiovascular Diseases, Shanghai, China. 9National Clinical Research Center for Intervention Medicine, Shanghai, China. 10These authors contributed equally: Mei Hua Ting, Huipeng Zhang, Siyuan Liu. ✉email: ; ; ; Received: 23 September 2025 Revised: 24 January 2026 Accepted: 9 February 2026 M.H. Ting et al. 2 Fig. 1 Integrative therapeutic landscape for spatiotemporal cardiac repair enabled by smart biomaterials. This schematic summarizes the solution space in which diverse therapeutic cargoes, including small molecules, nucleic acids, and cell-derived or vesicle-derived agents, are integrated with advanced delivery platforms such as nanoparticles, injectable hydrogels, patches, and bioinspired carriers to achieve spatially and temporally aligned intervention after myocardial infarction. Delivery interfaces span systemic, catheter-based, and local in situ routes, enabling differential engagement with key reparative processes including inflammation modulation, angiogenesis, and fibrotic remodeling across distinct post-infarction phases. Rather than presupposing specific mechanisms or outcomes, the figure illustrates how biomaterialenabled delivery platforms provide a unifying framework to match therapeutic action with the evolving biological demands of the injured myocardium. EV extracellular vesicle, miRNA microRNA, siRNA small interfering RNA, TGF-β transforming growth factor, VEGF vascular endothelial growth factor, NRG-1 neuregulin-1, FGF fibroblast growth factor, CO cardiac output, FS fractional shortening. biological potential and effective engagement of injured myocardium. However, successful cardiac repair depends not only on what is delivered but on when, where, and under what biological conditions therapy is active. Post-infarct (...truncated)