A Mitochondrion‐Targeting Piezoelectric Nanosystem for the Treatment of Erectile Dysfunction via Autophagy Regulation

Abstract Mitochondrial damage caused by external stimuli, such as high glucose levels and inflammation, results in excessive reactive oxygen species (ROS) production. Existing antioxidants can only scavenge ROS and cannot address the root cause of ROS production, namely, abnormal mitochondria. To overcome this limitation, the study develops a piezoelectric synergistic drug‐loaded nanosystem (BaTCG nanosystem) that targets mitochondria. The BaTCG nanosystem is delivered to mitochondria via triphenylphosphine modification, and generates current under the stimulation of ultrasound, thereby promoting mitochondrial autophagy and restoring mitochondrial homeostasis. In a model of diabetes‐related erectile dysfunction (ED), the BaTCG nanosystem, through the current induced by the piezoelectric effect, not only promoted mitophagy, thereby reducing ROS production, but also released long‐acting glucagon‐like peptide‐1 receptor agonists (GLP‐1RAs) to effectively reduce blood glucose levels and mitochondrial damage. Each component of this nanosystem functions individually as well as synergistically, thus facilitating corpus cavernosum repair and restoring erectile function. In conclusion, the findings offer a novel therapeutic strategy for diabetes‐related ED and a target for the treatment of diabetes‐related conditions with functionalized nanoparticles to regulate mitophagy.