Host-Response Engineering in Regenerative Cardiology: Mechanistic Boundaries Between Remuscularization and Immune Reprogramming

Regenerative cardiology has bifurcated into true remuscularization and host-response engineering. The first uses pluripotent-stem-cell-derived cardiomyocytes or engineered heart muscle to achieve durable contractile replacement; the second comprises adult stromal-cell products, extracellular vesicle preparations and biomaterials that may redirect endogenous repair without generating meaningful myocardium. This mechanistic narrative review reconstructs post-ischemic sterile inflammation as a temporally and spatially organized program and evaluates whether these platforms converge on shared causal pathways. Evidence is classified claim by claim using separate descriptive categories for therapeutic efficacy and mechanistic causal support. The platforms diverge proximally through administered-cell death and clearance, vesicle biodistribution and cargo transfer, or material–tissue interactions. Their most defensible distal convergence is incomplete and centers on monocyte/macrophage balance, efferocytosis, immune–fibroblast signaling and the macrophage–fibroblast–extracellular-matrix axis. Causal support is strong for selected mediators and preparations but cannot be generalized across product classes. No cross-platform convergence on therapeutically meaningful cardiomyocyte generation has been demonstrated. Human studies show limited target-engagement signals without evidence that they localize to myocardium or mediate benefit. Route, timing, disease stage and product identity should therefore be treated as mechanistic variables in preclinical design and clinical translation.