Synaptic Vesicle-Mimetic Exosomes Conjugated with -synuclein antibody for brain targeting delivery of miRNA and Dopamine reverse PD by Clear-and-Replenish dual actions
Parkinsons disease (PD) is a multifactorial neurodegenerative disorder driven by -synuclein (-syn) aggregation, dopaminergic neuron loss, and oxidative stress. Current monotherapies offer limited symptomatic relief and often necessitate dose escalation without halting disease progression. While multi-target strategies hold promise to address incurable diseases, the synchronous brain accurate delivery of multiple therapeutics with heterogeneous physicochemical properties remains a formidable challenge. Herein, we present a new triple-action biomimetic nanoplatform (SA-GEV-L) engineered from Gastrodia elata-derived exosomal vesicles (GEVs) for the precise delivery of multiple-therapeutic components to PD site. GEVs intrinsically encapsulated with neuroprotective miRNAs and further loaded with L-Dopa, with the surface functionalized by Synaptotagmin-1 (SYT1) via thiolmaleimide click chemistry and -syn antibody conjugation. While the surface modifications provide precise targeting and synaptic-like cellular uptake, the ROS-sensitive crosslinking ensures on-demand release of multiple payloads within the PD microenvironment. SA-GEV-L successfully executes a clear-and-replenish mode by accurately delivering both of the therapeutic miRNAs to clear the -syn aggregates and unblock cellular transport, and the L-Dopa to replenish dopamine level. SA-GEV-L treatment was shown to significantly outperformed classical L-Dopa therapy in restoring the motor functions, -syn degradation, and dopaminergic neurons regeneration in PD mice. SA-GEV-L integrates the synaptic vesicle biomimetic delivery, PD pathology-responsive cargoes orchestration, as well as the accurate engagement of multi-biotargets, establishing a potent new therapeutic paradigm for combating multi-factorial brain neurodegenerative diseases.