EXOSOME-MEDIATED DELIVERY OF PARKIN RESCUES MITOCHONDRIAL DYSFUNCITON IN PARKINSON’S DISEASE

Parkinson’s disease (PD) is characterized by impaired dopamine release and mitochondrial dysfunction, frequently associated with mutations in the Parkin (PRKN; PARK2) gene. Parkin is an E3 ubiquitin ligase essential for mitochondrial quality control, making it an attractive therapeutic target. In this study, we developed a protein delivery strategy using engineered extracellular vesicles (EVs) to transport Parkin and restore mitochondrial function in PD models. Specifically, we utilized photocleavable proteins to enable light-controlled release of Parkin from EVs, allowing precise activation of therapeutic function.

Engineered EVs were generated by inserting a photocleavable protein between Parkin and an exosomal membrane protein. Upon exposure to light of a specific wavelength, the photocleavable linker was cleaved, resulting in the release of Parkin into the EV lumen. The therapeutic efficacy of Parkin-loaded EVs was evaluated by assessing mitochondrial clearance and oxidative stress in cellular models of PD.

Light-induced release of Parkin from engineered EVs significantly improved mitochondrial quality in PD models. Treatment with Parkin EVs enhanced the clearance of damaged mitochondria and markedly reduced oxidative stress levels, demonstrating effective rescue of mitochondrial dysfunction.

This study presents a novel EV-based protein delivery platform for targeting mitochondrial defects in PD. By integrating photocleavable proteins, we achieved efficient loading and controlled release of therapeutic Parkin within EVs. Our findings highlight the potential of engineered EVs as a promising therapeutic strategy for early-onset autosomal recessive PD associated with mitochondrial dysfunction.