Extracellular Vesicle‐Mediated Delivery of Constrained Peptides Disrupts the Pathogenic Interaction of LRRK2‐FADD in Parkinson's Disease

The interaction between mutated leucine-rich repeat kinase 2 (LRRK2) and the death adaptor protein FADD accounts for apoptotic death of dopaminergic neurons in familial Parkinson's disease (PD) driven by LRRK2 mutations. Disrupting this pathogenic interaction using constrained peptides is a promising therapeutic strategy to mitigate apoptotic neuronal death in PD. However, efficiently delivering these therapeutic peptides to disease-relevant cells within the central nervous system (CNS) remains challenging due to degradation in circulation and poor blood-brain barrier and cell membrane penetration. Here, we present a strategy to use extracellular vesicles (EVs) as delivery vehicles for the therapeutic peptides to enhance their cellular uptake and CNS targeting. Following an optimized passive loading approach, we successfully packaged these peptides into EVs, improving their cellular uptake by disease-relevant neural cells in vitro and brain biodistribution in mice following intravenous administration. EV-based delivery enhanced the therapeutic efficacy of these peptides in disrupting FADD-LRRK2 interactions, reducing downstream caspase signaling and neuronal death in cellular models of PD compared to the free peptide format. These findings support the use of EVs as a promising shuttle for peptide-based therapies in PD and potentially other neurological disorders.