Abstract

Myocardial infarction (MI) initiates sterile inflammation through the release of cytosolic DNA from necrotic cardiomyocytes, which aberrantly activates the cGAS-STING pathway in infiltrating macrophages and drives their polarization toward a pro-inflammatory M1 phenotype. Although the immunosuppressive oligodeoxynucleotide A151 can antagonize cGAS activation, its therapeutic utility is limited by enzymatic instability and inefficient cellular delivery. Here, we report a dual-biomimetic nanodecoy (A151@APPL) that integrates platelet membrane vesicles for infarct-specific targeting with arginine-modified phosphatidylserine lipids to promote macrophage uptake and enable nitric oxide-driven propulsion in redox-enriched tissue. This construct achieves efficient cytosolic delivery of A151 to lesional macrophages, suppressing the cGAS-STING axis, reducing pro-inflammatory cytokine expression, and reprogramming macrophages toward a reparative M2-like state. In a murine MI model, A151@APPL treatment attenuated ventricular inflammation, limited fibrotic remodeling, and restored cardiac performance. These findings establish a context-responsive delivery strategy that selectively modulates innate immune signaling and promotes cardiac repair following ischemic injury.