Photocatalytic proximity labeling in primary samples

Primary samples, including freshly isolated cells, tissues, and clinical specimens, preserve native physiological states and microenvironments, making them especially valuable for understanding biological systems in health and disease. Proximity labeling (PL) has emerged as a powerful strategy for interrogating molecular interaction networks in situ, but conventional enzyme-based approaches are often difficult to apply to primary samples due to their reliance on genetic manipulation and sustained exogenous expression. Photocatalytic proximity labeling (PPL) provides a non-genetic alternative in which small-molecule photocatalysts activate labeling probes under light irradiation, enabling temporally gated and spatially localized covalent tagging of proximal biomolecules in a wide range of contexts. This review summarizes recent developments in the application of PPL to primary samples, spanning organelle-resolved proteomics, cell surface protein interaction profiling, cell-cell interaction analysis in tissues and in vivo, and emerging immune-engineering applications. While a growing diversity of photocatalytic systems and probe chemistries has been reported, their evaluation and deployment in primary cells and tissues remain at an early stage, reflecting the heightened demands for efficiency, specificity, and robustness in native biological contexts. We discuss how advances in reaction chemistry, catalyst targeting, and long-wavelength activation are beginning to address these challenges, and we outline key opportunities and limitations for extending PPL toward broader use in primary samples. Continued development of primary-oriented photocatalytic toolkits is expected to facilitate more direct interrogation of native biological systems, providing valuable insights into cellular organization, tissue-level communication, and disease-associated molecular remodeling.