Photolysis reactions are designed to preferentially occur in polar aqueous environment to accommodate biological applications. Described herein is a collection of aminobenzoquinone based photocages with accelerated photolytic kinetics in non-polar conditions. Structural investigation demonstrates the role of cyclic ring size, steric substituent, and electronic effect in regulating the reaction kinetics (KH2O & Kdioxane) and polarity preference (Kdioxane/KH2O). Rational introduction of optimal moieties leads to up to 5.2-fold kinetic acceleration (61.4×10-2 min-1) and 21.7-fold non-polar selectivity. Photochemical spectroscopic characterizations and theoretical calculations together explain the rationales underlying structure-polarity relationship. Notably, the uncaged ortho-quinone methide product bears covalent reactivity to-wards diverse nucleophiles of a protein, primarily Cys (66.7%), revealed by tandem mass spectrometry. Eventually, such lipophilic photolysis reaction is applied to selective capture of proteome in proximity to lipid droplets (LDs) in human diseased liver tissues. Downstream proteomic profiling of labeled proteins uncovers inter-organellar interactions with LDs. This work exemplifies photolysis reactions can act on-demand by biological microenvironment in addition to optical regulations.