Popescu Andrei¹, Nakamura Aiko², Al-Mutairi Saeed³, Fernandes Beatriz⁴, Weber Jonas⁵, Marchand Sophie⁶
ABSTRACT:
Background: Ischemia-reperfusion (I/R) injury remains a major challenge in the management of acute myocardial infarction and cardiac surgery, often exacerbating tissue damage despite successful reperfusion. A central driver of I/R injury is mitochondrial dysfunction, characterized by oxidative stress, calcium overload, mitochondrial permeability transition pore (mPTP) opening, and bioenergetic collapse. Conventional antioxidant and anti-apoptotic therapies have shown limited efficacy due to poor subcellular targeting. Recent advances in nanotechnology have enabled the development of mitochondria-targeted nanotherapeutics capable of delivering bioactive molecules directly to dysfunctional mitochondria, offering a new paradigm for cardioprotection. Methods and Results: This study evaluated a panel of engineered nanoparticle formulations, including triphenylphosphonium (TPP)-modified liposomes, mitochondria-penetrating peptide (MPP)-based carriers, and pH-sensitive polymeric nanoparticles loaded with antioxidants, mitophagy inducers, and permeability transition pore inhibitors. In preclinical models of myocardial I/R injury, these nanocarriers demonstrated enhanced mitochondrial uptake, reduced ROS generation, preserved membrane potential, and suppressed cytochrome c release. Histological and echocardiographic analysis confirmed reduced infarct size and improved ventricular function. Mechanistic studies revealed modulation of mitochondrial quality control pathways, including PINK1–Parkin–mediated mitophagy and AMPK–PGC1α axis activation. Conclusion: Mitochondria-targeted nanotherapeutics represent a promising strategy to address the unmet need for effective treatment of myocardial I/R injury. By bypassing systemic dilution and achieving precise subcellular delivery, these nanoplatforms restore mitochondrial homeostasis, attenuate cell death, and improve cardiac recovery. This study supports further development of mitochondria-specific delivery systems as next-generation cardioprotective interventions with translational potential.