Reticular Chemistry‐Enabled Sonodynamic Activity of Covalent Organic Frameworks for Nanodynamic Cancer 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 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. Two inactive monomers incapable of generating singlet oxygen under ultrasound (US) irradiation were utilized for the reticular synthesis of a backbone‐active covalent organic framework (COF) sonosensitizer (TPE‐NN) with intrinsic sonodynamic activity. With Cu ions coordination, the fabricated TPE‐NN‐Cu is demonstrated to exhibit a bilaterally enhanced nanodynamic feature of Cu ion‐augmented sonodynamic activity and US‐amplified chemodynamic catalytic efficacy.