A NADH Oxidase Nanozyme Restores Redox Homeostasis to Ameliorate Multi-Organ Aging and Ischemic Cardiomyopathy.

Redox imbalance resulting from NAD(+) [nicotinamide adenine dinucleotide (oxidized form)] depletion and NADH (reduced form of NAD(+)) accumulation is a conserved hallmark of both aging and myocardial infarction (MI), promoting cellular senescence and limiting the efficacy of regenerative therapies. Despite several NADH oxidase (NOX)-mimetic nanozymes having been reported, their therapeutic utility in aging and cardiovascular repair remains largely unexplored. Here, we present a vanadium-based nanozyme (MXene-TA) that mimics bacterial NOX activity, catalytically oxidizing NADH to restore NAD(+) and directly fixing redox imbalance. In aged (24-month-old) mice, systemic MXene-TA administration restored NAD(+)/NADH homeostasis and reduced senescence markers (p16, p21, γH2AX, and SASP) in the heart, liver, and spleen, yet this effect was not observed in the lungs or kidneys, indicating organ-specific redox susceptibility. In a rat MI model, local injection of MXene-TA into the infarcted myocardium reprogrammed metabolism, activated NAD(+)-dependent pathways, attenuated oxidative damage in cardiomyocytes, decreased infarct area, and enhanced myocardial function. To further enhance stem cell retention and function, we embedded MXene-TA and adipose-derived stem cells (ADSCs) into a pH-responsive, conductive hydrogel that mimics cardiac mechanical and electrical properties. This platform extended ADSC survival beyond 4 weeks (versus 1 week in controls) and further improved cardiac repair. Together, these findings uncover the therapeutic potential of NOX-mimetic nanozymes in aging and ischemic heart disease and introduce a redox-regulating hydrogel system that addresses both oxidative stress and stem cell integration for effective myocardial repair.