Subcellular photochemistry for precision spatial protein targeting

Proteins with conserved active sites but distinct subcellular localizations, such as mislocalized variants, splicing isoforms and isozymes, are prevalent in disease. However, conventional drug design lacks the spatial control needed for their selective targeting. Subcellular photochemistry offers a solution. Light-activated catalysts with spatiotemporal control convert inert prodrugs into active drugs at the desired subcellular location, without affecting conserved proteins at native sites. In this Perspective, we discuss challenges of targeting mislocalized proteins, principles of subcellular photochemistry for site-specific intervention, strategies for anchoring photocatalysts and key examples of subcellular photocatalytic prodrug activation for precision targeting. We also examine limitations of this approach and propose future solutions. This strategy is expected to expand the druggable target repertoire and advance precision medicine.