Targeted Delivery of AGO-2 to Myocardial Mitochondria via Functionalized Nanoparticles Attenuates Oxidative Stress in Diabetic Cardiomyopathy

Mitochondrial dysfunction is a hallmark of early diabetes. Previous studies suggest that Argonaute-2 (AGO-2) supplementation enhances mitochondrial gene expression and improves cellular stability. Here, we investigated AGO-2 expression during diabetic myocardial injury and designed a multifunctional nanocarrier to selectively deliver AGO-2 to cardiac mitochondria, aiming to restore mitochondrial homeostasis and mitigate oxidative stress. We employed an extremely small iron oxide (ESIO) nanoparticle core functionalized with cardiac-homing peptide (CHP) and the mitochondrial-targeting peptide SS-31 to construct a targeted platform, denoted ESIO-SS-31-CHP (ESC). AGO-2 was stably incorporated via phenylboronic acid by B-N binding, yielding ESC-AGO-2. Structural and functional characterizations demonstrated efficient targeting and carrier stability. In diabetic mice, AGO-2 localization in mitochondria was downregulated at 4 weeks and exhibited impaired mitochondrial translocation. ESC-AGO-2 effectively localized to mitochondria in vitro and in vivo, leading to improved mitochondrial performance, reduced oxidative damage, and attenuated inflammatory responses. These findings highlight AGO-2 as a potential biomarker for early diabetes and introduce ESC-AGO-2 as a promising nanomedicine strategy for precision intervention at the onset of diabetic cardiomyopathy.