A Biological Channel‐Inspired Ultrasound‐Responsive Metabolism Nanoswitch for Unleashing Cancer Sonometabolism Therapy

Abstract Metabolic dysregulation is a pivotal feature of cancer progression, providing opportunities for advancing cancer treatment. Herein, inspired by the biological channels, an ultrasound‐responsive metabolism nanoswitch (MetaSwitch) is developed that can open a sonometabolism therapy to improve the management of malignancy through manipulating cellular metabolic pathways. MetaSwitch has a biomembrane‐like architecture, consisting of dichloroacetic acid (DCA) loaded sonoactive COFs (Py‐AD‐TZ), and an RGD peptide‐functionalized PEG surface layer. Notably, benefiting from the alternating electron donor–acceptor fully conjugated structures in Py‐AD‐TZ, MetaSwitch exhibits great sonodynamic activity. In addition, MetaSwitch is filled with biomimetic nanochannels with ultrasound gating effect, which can intelligently control the release of DCA, thereby altering the glucose metabolism of cancer cells from aerobic glycolysis to normal oxide phosphorylation. Moreover, this metabolic remodeling directly downregulates the expression of antiapoptotic proteins, and reactivates the cellular apoptotic pathway, which greatly sensitizes cells to ultrasound‐mediated oxidative stress, resulting in substantial cancer cell death. Importantly, in vivo studies demonstrate that MetaSwitch selectively accumulates in the tumor, and efficiently induces tumor inhibition and even abrogation under the mild ultrasound stimulation, leading to prolonged survival period of tumor‐bearing mice. Therefore, MetaSwitch provides a paradigm to design smart COFs‐based platforms for safe and efficient cancer therapy.