Spatiotemporally Orchestrated Cardiac Microneedle Patch Modulates Post-Infarction Immunity and Fibrosis

Myocardial infarction (MI) remains a leading cause of morbidity and mortality worldwide. Following MI, the initial inflammatory cascade may cause secondary myocardial injury, with excessive fibrosis subsequently leading to long-term functional impairment. To rationally address the dynamic post-MI pathology, we screened nine representative metal ions and identified magnesium (Mg²⁺) as a potent protective ion against hypoxia-induced cardiomyocyte injury and inflammation. We then developed a spatiotemporally orchestrated, dissolvable microneedle patch (Mg-AAV-MN) for smart drug delivery to mitigate both early inflammation and late fibrosis. This system comprised two core functional modules aligned with the post-MI pathological phases: A fast-acting "Pioneer Module" comprising Mg²⁺-loaded lipid nanoparticles to modulate the early inflammatory microenvironment during the inflammatory phase, and a sustained "Sustainer Module" enabling adeno-associated virus-mediated interleukin-10 delivery to suppress aberrant fibroblast activation and limit pathological fibrosis during the remodeling phase. A "bead-like" structure was designed to ensure precise, sustained drug delivery to the beating heart. In vivo studies validated that Mg-AAV-MN significantly reduced infarct size, improved cardiac function, and mitigated adverse ventricular remodeling. This spatiotemporally orchestrated design addresses the limitation of a single therapeutic time window, achieving temporally phased and spatially confined management of the entire MI repair cycle.