Abstract Singlet oxygen ( 1 O 2 )‐mediated specific reactions play vital roles in numerous applications. However, the typically co‐existed reactive oxygen species (ROS, mainly superoxide anion, O 2 •− and hydroxyl radical, •OH) during photosensitization can cause interferences to above reactions. Herein, to boost the production yield and purity of 1 O 2 , this study develops a matrix‐based strategy that can propel the energy of type I to type II photosensitization. Lanthanide‐nucleotide coordination networks (CNs) are employed as the matrix for hosting organic photosensitizers (PSs, e.g., porphyrins and phthalocyanines). By isolating PSs from direct contact with H 2 O, the resulted PSs@CNs show about threefold 1 O 2 boosting, along with more than 80% decrease of O 2 •− . Using Ce 6 as the model PSs, the obtained Ce 6@CNs exhibit more efficient oxidation of tryptophan and phenol (both are seriously interfered by O 2 •− and •OH), and eventually achieve two advanced photo‐drugs: photo‐induced phospholipase A 2 enzyme inactivation for potential venom detoxification and in situ synthesis of chemo‐drug (juglone) for cancer therapy.