Bioenergetics-Driven Extracellular Vesicle Therapies for Heart Failure: From Preclinical Insights to Regenerative Translation.

Heart failure (HF) is fundamentally a disease of energetic insufficiency, in which impaired mitochondrial efficiency, maladaptive metabolic remodeling, and disrupted intercellular signaling converge at the organ level to limit cardiac performance. Despite advances in pharmacologic and device-based therapies, current treatment paradigms largely modulate hemodynamics or neurohormonal pathways rather than directly restoring myocardial bioenergetic capacity. Emerging evidence positions extracellular vesicles (EVs) as endogenous regulators of cardiac energy homeostasis, capable of orchestrating coordinated metabolic and mitochondrial adaptations across cardiac and non-cardiac cell populations. This review advances a system-level framework in which EVs are conceptualized as bioenergetic therapeutics, i.e., active biological agents that reprogram cellular energy utilization, substrate flexibility, and mitochondrial efficiency, rather than passive carriers of isolated molecular cargo. We synthesize preclinical evidence demonstrating EV-mediated modulation of oxidative phosphorylation, glycolytic balance, redox signaling, and mitochondrial dynamics, and examine how these effects scale from cellular and small-animal models to clinically relevant heart failure phenotypes. Importantly, we highlight organ-level integration, wherein EV signaling interfaces with vascular, immune, and metabolic networks to reshape myocardial energetic demand and supply. By bridging mechanistic insights with translational considerations, this review addresses the central question of how EV-driven bioenergetic reprogramming can be deployed within contemporary HF treatment paradigms. We propose EV-based strategies as complementary or synergistic interventions capable of restoring energetic resilience, reframing heart failure therapy beyond structural repair toward systemic metabolic renewal.