The development of covalent organic framework (COF) sonosensitizers with intrinsic sonodynamic effects is highly desirable. However, such COFs are generally constructed using small‐molecule photosensitizers. Herein, we report that the reticular chemistry‐based synthesis of COFs from two inert monomers yields a COF‐based sonosensitizer (TPE‐NN) with inherent sonodynamic activity. Subsequently, a nanoscale COF TPE‐NN is fabricated and embedded with copper (Cu)‐coordinated sites to obtain TPE‐NN‐Cu. Results show that Cu coordination can enhance the sonodynamic effect of TPE‐NN, whereas ultrasound (US) irradiation for sonodynamic therapy can augment the chemodynamic efficacy of TPE‐NN‐Cu. Consequently, TPE‐NN‐Cu upon US irradiation shows high‐performance anticancer effects based on mutually reinforced sono‐/chemo‐nanodynamic therapy. This study reveals the backbone‐originated sonodynamic activity of COFs and proposes a paradigm of intrinsic COF sonosensitizers for nanodynamic therapy.

The development of covalent organic framework (COF) sonosensitizers with intrinsic sonodynamic effects is highly desirable. However, such COFs are generally constructed using small-molecule photosensitizers. Herein, we report that the reticular chemistrybased synthesis of COFs from two inert monomers yields a COF-based sonosensitizer (TPE-NN) with inherent sonodynamic activity. Subsequently, a nanoscale COF TPE-NN is fabricated and embedded with copper (Cu)-coordinated sites to obtain TPE-NN-Cu. Results show that Cu coordination can enhance the sonodynamic effect of TPE-NN, whereas ultrasound (US) irradiation for sonodynamic therapy can augment the chemodynamic efficacy of TPE-NN-Cu. Consequently, TPE-NN-Cu upon US irradiation shows highperformance anticancer effects based on mutually reinforced sono-/chemo-nanodynamic therapy. This study reveals the backbone-originated sonodynamic activity of COFs and proposes a paradigm of intrinsic COF sonosensitizers for nanodynamic therapy.