Programmable gene modulation networks for Parkinson's disease using nanotechnology enabled CRISPR/Cas brain delivery

Parkinson's disease is a progressive neurodegenerative disorder driven by interconnected molecular pathways, including α-synuclein aggregation, mitochondrial dysfunction, impaired proteostasis, and neuroinflammation. Current therapies are primarily symptomatic and have not consistently demonstrated prevention of disease progression. This review introduces Programmable gene modulation networks, a systems-level framework that integrates CRISPR/Cas technologies with nanotechnology-enabled brain delivery for precision intervention in Parkinson's disease. Advanced CRISPR modalities, including CRISPR interference, activation, base editing, prime editing, and epigenetic editing, are evaluated for reversible and targeted modulation of disease-relevant gene networks. Non-viral nanocarrier platforms, such as lipid nanoparticles, polymeric systems, and exosome-mimetic vesicles, are discussed for overcoming blood-brain barrier limitations and improving brain-specific delivery. The review further emphasizes translational challenges, including delivery efficiency, off-target effects, long-term safety, manufacturing scalability, and regulatory considerations. By integrating molecular network biology, programmable gene regulation, and translational decision-making, this review provides a roadmap for developing next-generation disease-modifying therapies for Parkinson's disease.