LAUSR

Covalent organic frameworks (COFs) have attracted increasing attention for biomedical applications. COFs‐based nanosensitizers with uniform nanoscale morphology and tumor‐specific curative effects are in high demand; however, their synthesis is yet challenging. In this study, distinct COF nanobowls are synthesized in a controlled manner and engineered as activatable nanosensitizers with tumor‐specific sonodynamic activity. High crystallinity ensures an ordered porous structure of COF nanobowls for the efficient loading of the small‐molecule sonosensitizer rose bengal (RB). To circumvent non‐specific damage to normal tissues, the sonosensitization effect is specifically inhibited by the in situ growth of manganese oxide (MnOx) on RB‐loaded COFs. Upon reaction with tumor‐overexpressed glutathione (GSH), the “gatekeeper” MnOx is rapidly decomposed to recover the reactive oxygen species (ROS) generation capability of the COF nanosensitizers under ultrasound irradiation. Increased intracellular ROS stress and GSH consumption concomitantly induce ferroptosis to improve sonodynamic efficacy. Additionally, the unconventional bowl‐shaped morphology renders the nanosensitizers with enhanced tumor accumulation and retention. The combination of tumor‐specific sonodynamic therapy and ferroptosis achieves high efficacy in killing cancer cells and inhibiting tumor growth. This study paves the way for the development of COF nanosensitizers with unconventional morphologies for biomedicine, offering a paradigm to realize activatable and ferroptosis‐augmented sonodynamic tumor therapy.