Opto-CRISPR technologies in translational neuropharmacology.

Abstract

Opto-CRISPR (optically controlled CRISPR/Cas) represents a major advancement in precision neurology by enabling localized gene editing within the nervous system at precise times and locations. While preclinical studies still rely largely on classical CRISPR/Cas systems, opto-CRISPR offers unprecedented opportunities to safely treat neurological diseases at their genetic roots. It achieves this by spatiotemporally correcting pathogenic mutations, halting toxic protein accumulation, repairing neurons, rebuilding neural circuitry, and accelerating drug discovery through highly realistic disease models. This review discusses this emerging field and its transformative potential for translational neuropharmacology, focusing on therapies for neurodevelopmental and neurodegenerative disorders. Opto-CRISPR is classified into four generations: Generation 1 (light-controlled Cas protein systems), Generation 2 (light-activated guide RNA systems), Generation 3 (light-controlled inhibitor systems), and Generation 4 (NIR upconversion and epigenetic multiplexing). Their working mechanisms, applications, advantages, and limitations are comprehensively described. We also critically discuss how opto-CRISPR offers distinct advantages over traditional biologics and remote modalities (e.g., small-molecule drugs, monoclonal antibodies, antisense oligonucleotides, viral-mediated gene therapy, magnetogenetics, and sonogenetics) in neuropharmacology. Finally, we address current challenges and the therapeutic outlook for the clinical translation of opto-CRISPR.