Nanotechnology for targeted modulation of mitophagy: molecular mechanisms, therapeutic applications, and...

Mitophagy is a selective autophagic process responsible for the elimination of damaged or dysfunctional mitochondria, playing a critical role in maintaining mitochondrial quality control and cellular homeostasis. Dysregulated mitophagy has been implicated in the pathogenesis of numerous diseases, including neurodegenerative diseases, cancer, cardiovascular diseases, metabolic disorders, inflammatory and immune diseases, and musculoskeletal diseases. In recent years, nanotechnology-based approaches for the targeted modulation of mitophagy have emerged as promising therapeutic strategies due to their ability to achieve precise regulation, enhanced subcellular targeting, and reduced off-target effects. Building upon advances in the understanding of mitophagy mechanisms, a variety of nano-delivery systems have been developed, incorporating strategies such as mitochondria-targeting, stimuli-responsive activation, ligand-mediated targeting, and combination therapies. However, a comprehensive review integrating the molecular mechanisms of mitophagy, disease-specific therapeutic applications, nanoplatform design strategies, and translational challenges remains lacking. The present review provides an integrated overview of the molecular regulatory mechanisms of mitophagy, summarizes recent advances in nanotechnology-based therapeutic interventions across multiple disease types, and critically discusses current nanoplatform design strategies. Furthermore, key challenges associated with mitophagy evaluation, biosafety, pharmacokinetics, clinical translation, and regulatory considerations are highlighted, together with emerging technologies that may accelerate the development of next-generation mitophagy-targeting nanomedicines.