Dual-biomimetic Nanodecoys reprogram cardiac macrophages by suppressing STING signaling for heart repair

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.