Spatiotemporal precision interventions for cardiac repair and regenerative therapy.

Figures

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  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 biomaterial-enabled 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…

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  Fig. 2. Spatiotemporal progression of myocardial infarction and post-infarction healing. The myocardial response to infarction unfolds through overlapping inflammatory (days 0–3), proliferative (days 4–7), and remodeling (day 7 onwards) phases, each characterized by distinct immune, cellular, and extracellular matrix dynamics. In the infarct core, cardiomyocyte necrosis triggers damage-associated molecular pattern (DAMP) signaling, acute inflammatory cell infiltration, oxidative stress, and matrix degradation, followed by fibroblast activation and scar formation. The peri-infarct border zone represents a biologically active interface in which immune modulation, angiogenesis, and matrix remodeling coexist, supporting tissue stabilization but remaining sensitive to dysregulated intervention. By contrast, the remote myocardium undergoes progressive secondary remodeling driven by altered loading and neurohumoral signaling, including cardiomyocyte hypertrophy and interstitial fibrosis, which impair contractile and electrical function. These temporally and spatially heterogeneous processes define a dynamic therapeutic landscape that constrains the timing, localization, and duration of…

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  Fig. 3. Evolution of pharmacological management in heart failure with reduced ejection fraction. This timeline highlights key clinical trials, guideline endorsements, and regulatory approvals that have shaped contemporary HFrEF management. Several drug classes now central to GDMT, including RAAS modulators, β-blockers, MRAs, and SGLT2i, were initially developed for other indications and later repurposed or expanded following mechanistic and clinical insights. The progressive incorporation of ARNIs and SGLT2i reflects a shift toward cardiometabolic and multisystem modulation rather than disease-specific targeting alone. Collectively, this evolution illustrates how therapeutic impact can be transformed without introducing new molecular entities, providing a precedent for reformulating existing cardiovascular drugs using advanced DDS to improve myocardial selectivity, reduce off-target exposure, and further personalize therapy. ACC/AHA American College of Cardiology/American Heart Association, ACEI angiotensin-converting enzyme inhibitor, ARB angiotensin receptor blocker, ARNI angiotensin receptor–neprilysin inhibitor, DDS drug delivery system, EF ejection fraction, ESC European Society for…

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  Fig. 4. Future directions in spatiotemporal drug delivery for cardiac repair and regeneration. Next-generation spatiotemporal drug delivery systems (DDS) are evolving toward multifunctional and adaptive platforms capable of aligning therapeutic activity with the dynamic biology of post-infarction healing. Key trajectories include biosensor-integrated systems that enable real-time, feedback-controlled release; phase-specific combinatorial delivery platforms synchronized with inflammatory, proliferative, and remodeling stages; electroconductive biomaterials that support electromechanical coordination; and scalable, cell-free vesicle-based therapies that enhance translational feasibility. Parallel advances in minimally invasive delivery technologies, artificial intelligence (AI)-guided design, and harmonized regulatory and manufacturing frameworks are expected to accelerate clinical translation and support more precise, personalized cardiac therapy.