Diselenide Nanogels Modulate Mitochondrial Function and Mitigate Oxidative Stress in Cardiomyocytes for Enhanced Cardiac Repair

Mitochondrial dysfunction and oxidative stress are pivotal factors contributing to the loss of cardiac function following heart injury, yet these aspects are frequently underappreciated in the medication design paradigm. Here we have developed diselenide-cross-linked zwitterionic nanogels to restore mitochondrial homeostasis and boost energy supply for damaged heart repair. These nanogels exhibit an enhanced circulation time within the bloodstream post systemic administration and have been observed to concentrate at the site of the damaged myocardium in both myocardial infarct (MI) rat model and cardiotoxic mouse model. Our mechanistic investigations have revealed that these nanogels have the capacity to mitigate the oxidative microenvironment, thereby preserving the mitochondrial function of cardiomyocytes. Moreover, the degradation products of these nanogels have been shown to upregulate intracellular ATP synthesis, which in turn increases cardiac contractility and promotes the recovery of cardiac function. The innovative nanogel system presented herein holds significant potential for clinical translation, offering a therapeutic strategy for the restoration of cardiac function and a fresh perspective on maintaining energy metabolism homeostasis in the treatment of heart injury.