biostudies-literatureShen DMOST | National Natural Science Foundation of China (NSFC)MOST | National Natural Science Foundation of Chinae2420861122https://www.ebi.ac.uk/biostudies/studies/S-EPMC12037041biostudies-literatureUnknown122(16)Most bioorthogonal photouncaging reactions preferentially occur in polar environments to accommodate biological applications in the aqueous cellular milieu. However, they are not precisely designed to chemically adapt to the diverse microenvironments of the cell. Herein, we report a hydrophobic photouncaging reaction with tailored photolytic kinetics toward solvent polarity. Structural modulations of the aminobenzoquinone-based photocage reveal the impact of cyclic ring size, steric substituent, and electronic substituent on the individual uncaging kinetics (<i>k</i>_H2O and <i>k</i>_dioxane) and polarity preference (<i>k</i>_dioxane/<i>k</i>_H2O). Rational incorporation of optimized moieties leads to up to 20.2-fold nonpolar kinetic selectivity (<i>Proceedings of the National Academy of Sciences of the United States of AmericaA hydrophobic photouncaging reaction to profile the lipid droplet interactome in tissues.PMC12037041222071062237414822222410Dong XZhang HWu CShen DZhang LLiu YJin HGuo KZhao QSun RGuo HFeng HGao ZfalseA hydrophobic photouncaging reaction to profile the lipid droplet interactome in tissues.Most bioorthogonal photouncaging reactions preferentially occur in polar environments to accommodate biological applications in the aqueous cellular milieu. However, they are not precisely designed to chemically adapt to the diverse microenvironments of the cell. Herein, we report a hydrophobic photouncaging reaction with tailored photolytic kinetics toward solvent polarity. Structural modulations of the aminobenzoquinone-based photocage reveal the impact of cyclic ring size, steric substituent, and electronic substituent on the individual uncaging kinetics (<i>k</i>_H2O and <i>k</i>_dioxane) and polarity preference (<i>k</i>_dioxane/<i>k</i>_H2O). Rational incorporation of optimized moieties leads to up to 20.2-fold nonpolar kinetic selectivity (<i>2025-01-01T00:00:00Z2025 Apr2026-06-04T12:08:36.961Z2026-05-09T03:08:11.709ZS-EPMC120370414023845910.1073/pnas.2420861122