A sonopiezoresponsive covalent organic framework-based smart nanoreactor orchestrates in situ bioorthogonal chemistry and cuproptosis for enhanced tumor therapy

Piezocatalytic therapy (PCT) has garnered increasing interest in the field of cancer treatment. However, its therapeutic efficacy is hampered by the limitations of current piezoelectric materials and the intrinsic therapeutic resistance of tumors. Here, leveraging elaborately designed copper-coordinated covalent organic frameworks (CuCOF-2 N) as piezocatalysts, a smart ultrasound-controlled nanoreactor (Cu2N@D-FA) is constructed by co-encapsulating with doxorubicin prodrug into folic acid-modified liposomes, to enhance the antitumor efficacy of PCT through the combination of cuproptosis and bioorthogonal catalysis. The structure-property comparison with related COFs underscores the important role of highly polar triazine rings and symmetry-disrupting bidentate ligands in enhancing piezoelectric performance of CuCOF-2 N. Upon ultrasound irradiation, CuCOF-2 N not only produces hydroxyl radicals independently of oxygen but also enables a self-sustained oxygen supply for generating superoxide anions and singlet oxygen, which surmount constraints of traditional piezoelectric materials to trigger strong PCT. Moreover, the mediated-copper valence switching in CuCOF-2 N permits spatiotemporally precise bioorthogonal catalysis and triggers cuproptosis, overcoming therapeutic limitations and amplifying the PCT effect. In vivo studies demonstrate that Cu2N@D-FA selectively accumulates in the tumor and effectively eliminates the tumor without side-effects under US stimulation. Therefore, this study highlights the great promise of COFs in piezocatalysis and offers a paradigm for enhancing PCT. STATEMENT OF SIGNIFICANCE: A sonopiezoresponsive copper-coordinated covalent organic framework is designed and co-encapsulated with a doxorubicin prodrug in folic acid-modified liposomes to enable synergistic piezocatalytic therapy. The CuCOF enables oxygen-independent hydroxyl radical generation while providing a self-sustained oxygen supply for the production of superoxide anions and singlet oxygen. Ultrasound triggers reversible valence state switching of copper within the framework, enabling in situ bioorthogonal catalysis, and the concomitant mitochondrial accumulation of copper induces cuproptosis. The CuCOF-based nanoreactor demonstrates good biocompatibility and achieves potent tumor suppression under mild ultrasound irradiation.