Covalent organic frameworks (COFs) and their derivatives represent an emerging class of crystalline porous materials with broad potential applications. However, the biomedical applications of them were limited by the large size, low dispersivity, poor bioavailability within cells and metabolic problems. Herein, renal-clearable ultrasmall COF nanodots have been synthesized and utilized as efficient cancer therapy agents. A simple liquid exfoliation strategy was used to prepare COF nanodots. After polyethylene glycol (PEG) conjugation, the PEG coated COF nanodots (COF nanodots-PEG) showed improved physiological stability and biocompatibility. In addition, the well isolated porphyrin molecules endowed COF nanodots-PEG good light-triggered reactive oxygen species production ability, which showed excellent photodynamic therapy efficiency with good tumor accumulation ability. In particular, due to the ultrasmall size, COF nanodots-PEG could be cleared from the body through the renal filtration with no appreciable in vivo toxicity. Our study highlights the potential of COFs-based nanoparticles for biomedical applications.