Magneto-controllable cell robots for targeted myocardial infarction repair

Myocardial infarction (MI) triggers irreversible cardiomyocyte loss, maladaptive remodeling, and heart failure processes exacerbated by insufficient endogenous angiogenesis and unresolved inflammation. While pro-angiogenic therapies hold promise, their clinical translation is hindered by poor lesion targeting, subtherapeutic drug accumulation, and transient bioactivity. To overcome these barriers, we engineered "magnetically guided cellular robots", M2a-polarized macrophages intracellularly loaded with superparamagnetic Fe₃O₄ nanoparticles and genetically programmed for sustained VEGF secretion (Mag-M2). Mag-M2 exhibits dual responsiveness: chemotactic homing to ischemic myocardiumandprecise magnetic navigation under a 0.5-T field, enabling enhanced transendothelial migration and deep infarct-zone penetration. In MI models, intravenous Mag-M2 administration followed by magnetic guidance significantly preserved left ventricular ejection fraction (67.8 % vs. 40.7 %), reduced infarct size (25.96 % vs. 37.67 %), attenuated fibrosis, and improved survival without systemic toxicity. Mechanistically, Mag-M2 activates a novel VEGF/METRNL/KIT axis: VEGF upregulates the adipokine METRNL, which acted as a high-affinity KIT ligand, driving peri-infarct neovascularization and suppressing pro-inflammatory cytokines (IL-1β, IL-6, TNF α). This integrative platform synergizes immunomodulation, magnetic targeting, and pathway-specific regenerative signaling, offering a rationally designed, translatable strategy for precision myocardial repair.