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

Abstract

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. This study constructs a cardiomyocyte-specific APT-modified biomimetic NP. This work is associated with modulation of the Mst1-autophagy-apoptosis signaling axis in DCM. This study validates, using both in vitro and in vivo models, that the NP promotes mitochondrial homeostasis and restores energy metabolism. The study elucidates the mechanisms of myocardial energy reprogramming through multi-omics analyses. This study systematically evaluates the biosafety of the NP and confirms its favorable biocompatibility.