Restoring autophagy-apoptosis balance in diabetic cardiomyopathy via a biomimetic, ROS-responsive nanocarrier associated with Mst1 pathway modulation.

Diabetic cardiomyopathy (DCM) is driven by oxidative stress and an imbalance between autophagy and apoptosis. To improve myocardial delivery of dimethyl fumarate (DMF), a known NRF2-activating redox modulator, and evaluate its association with Mst1 pathway regulation, we developed a cardiac-targeting peptide (APT)-modified biomimetic, reactive oxygen species (ROS)-responsive nanoplatform (NP-APT). NP-APT comprises a ROS-sensitive core and a lipid-cell membrane hybrid coating modified with APT to achieve targeted delivery. The designed nanoplatform demonstrated favorable physicochemical properties, serum/storage stability, macrophage-avoidance capability, and ROS-responsive drug release. In vitro, NP-APT enhanced cardiomyocyte uptake, mitigated high-glucose-induced oxidative stress, restored mitochondrial function and bioenergetic activity, and attenuated apoptosis. Mechanistically, NP-APT protected cardiomyocytes in association with reduced Mst1-related protein abundance, improved autophagy-related signaling, and rebalanced the autophagy-apoptosis equilibrium; Mst1 overexpression weakened these effects, whereas autophagy blockade reduced NP-APT-mediated protection. In a murine DCM model, NP-APT achieved cardiac-specific accumulation, significantly improved cardiac function and fibrosis, and restored cellular homeostasis, with efficacy associated with Mst1 pathway modulation. Hematological, biochemical, behavioral, and histological safety assessments indicated that NP-APT did not produce evident additional systemic toxicity under the tested treatment conditions in DCM mice. Collectively, this study demonstrates that APT-mediated biomimetic nanodelivery provides an effective strategy to enhance DMF myocardial delivery and ameliorate DCM in association with Mst1-autophagy-apoptosis pathway regulation.