Controlled release system based on mesoporous silica (MS) nanomaterials has drawn great attention over the past decades due to its potential biomedical applications. Herein, a light-responsive release system based on MS nanoparticles was achieved by adjusting the wetting of the MS surface. At the starting stage, the surface of MS modified with optimal ratio of spiropyran to fluorinated silane (MS-FSP) was protected from being wetted by water, successfully inhibiting the release of model cargo molecules, fluorescein disodium (FD). Upon irradiation with 365 nm UV light, the conformational conversion of spiropyran from a “closed” state to an “open” state caused the surface to be wetted, leading to the release of FD from the pores. The further in vitro studies demonstrated the system loaded with anticancer drug camptothecin (CPT) could be effectively controlled to release the drug by UV light stimuli to enhance cytotoxicity for EA.hy926 cells and HeLa cells. This wettability-determined smart release platform could be triggered by remote stimuli, which might hold promise in the applications of drug delivery and cancer therapy.