Photocatalytic Proximity Labeling Maps RNA and Protein Subcellular Landscapes.

Mapping the molecular landscapes within subcellular compartments is critical for understanding cellular function. Photocatalytic proximity labeling has emerged as an increasingly diversified chemical strategy for interrogating biomolecular microenvironments in living systems. However, a modular small-molecule platform that can be readily retargeted and used to capture both protein and RNA neighborhoods within specific organelles remains underdeveloped. Existing photocatalytic approaches have employed distinct probe-activation modes for biomolecular labeling. Here, PhotoPL adopts an oxidative activation design based on established selenide photooxidation chemistry within a modular organelle-targeted platform. This method employs an organelle-targeted photocatalyst and an activatable selenide probe. Upon visible light irradiation, the localized catalyst generates short-lived reactive intermediates that covalently tag proximal biomolecules. We successfully applied PhotoPL to profile the proteomes and transcriptomes of mitochondria and the endoplasmic reticulum (ER), validating the high-fidelity capture of organelle-specific molecules. Unlike enzyme-based methods, PhotoPL utilizes small-molecule components, minimizing cellular perturbation. Its key advantage is a modular, "plug-and-play" design that allows for rapid retargeting to new subcellular locations without laborious genetic cloning. This modular and scalable platform expands the current chemical toolbox for dissecting the molecular organization of cells and exploring the interplay between proteins and RNAs in health and disease.