Advancing Parkinson's Prevention: Brain-Specific Lipopolyplex Delivery of the GDNF as a Neuroprotective Gene Therapy.

Parkinson's disease (PD) is characterized by progressive dopaminergic neuron loss. Although the glial cell line-derived neurotrophic factor (GDNF) offers therapeutic promise, its clinical translation is hampered by challenges related to delivery methods and the timing of intervention. Here, we developed a brain-targeted lipopolyplex (BAGLPP) for systemic GDNF gene delivery. BAGLPP incorporates an RVG29 peptide-modified lipid shell for blood-brain barrier crossing and a polyethylenimine-condensed AAV plasmid core for efficient transfection. Following intravenous administration, BAGLPP demonstrated superior brain accumulation and expression in PD-relevant regions. In a cellular PD model, BAGLPP pretreatment reduced apoptosis, oxidative stress, and pathological α-synuclein (pS129) accumulation. In MPTP-induced mice, prophylactic BAGLPP treatment established sustained GDNF expression (maintaining levels 3.7-fold higher than controls at 8 weeks postlesion), which activated the PI3K/Akt pro-survival pathway, suppressed pro-apoptotic Bax, and attenuated neuroinflammation. This multifaceted protection preserved dopaminergic neurons and striatal dopamine and improved motor function without significant systemic toxicity. Our findings establish BAGLPP as a durable, nonviral gene therapy platform with strong potential for preventing PD progression.