Engineering a Green Fluorescent Protein-Core-Inspired NIR-Photocage: Exploring <i>meso</i>-GFP-PRPG toward Alzheimer’s Disease Therapeutics

NIR light-activated photocage with inherent protein tagging ability is unprecedented in contemporary photochemistry. Herein, we introduce a series of protein-taggable NIR-photocages derived from green fluorescent protein (GFP) chromophore analogs with spatiotemporal control for releasing the caged bioactive molecules. Through molecular engineering of the GFP chromophoric scaffold, a series of meso-substituted oxazolone-photocages (<i>meso</i>-GFP-PRPG) were judiciously designed and synthesized. These photocages, anchored with electron-donating groups (EDG) and electron-withdrawing groups (EWG), accommodate diverse payloads, including aliphatic carboxylic acids, expanding the possibilities for tailoring their properties and applications. Notably, under anaerobic conditions, irradiation of <i>meso</i>-GFP-PRPG leads to fast and efficient release of caged molecules. Insightful experimental and theoretical investigations revealed that photorelease is predominantly driven by the triplet state photochemistry in anaerobic conditions. The concept's theranostic potential was demonstrated by the conditional release of valproic acid, a neuroprotective agent for Alzheimer's disease (AD) treatment. <i>meso</i>-GFP-PRPG (<b>15E</b>) showed enhanced NIR emission with Aβ oligomers and fibrils (30-37 fold vs ThT) and effectively degraded amyloid fibrils under 640 nm light, offering a promising targeted treatment approach for neurodegenerative disorders.