Red light-responsive bioorthogonal chemistry enabled on-demand prodrug activation for cancer therapy.

Light-driven chemistry has revolutionized modern medicine, enabling precise disease detection and on-demand therapeutic interventions with high spatiotemporal accuracy. However, despite tremendous advances in bioorthogonal reactions, photoclick chemistry-based therapeutics remain as a challenge in vivo. To address this limitation, we have developed a multifunctional BODIPY-caged glucamine dihydrotetrazine (BGdTz) that integrates cancer-targeting, fluorescence imaging, and photoactivable tetrazine bioorthogonal chemistry. By targeting the overexpressed glucose transporter 1 (Glut1) on cancer cells, BGdTz specifically accumulates at the tumor site, leading to high-contrast fluorescence imaging of tumor in murine models. Subsequent irradiation of BGdTz with red light results in a spatialtemporal formation of glucamine-tetrazine. Furthermore, we have demonstrated an image-guided bioorthogonal prodrug activation between BGdTz and trans-cyclooctene caged doxorubicin, revealing potent antitumor efficacy and minimal systemic toxicity in A375 xenograft mouse models. In summary, we present a red light-controllable tetrazine bioorthogonal platform operable in mammals, offering a powerful tool for dual cancer diagnosis and therapy. We anticipate that this photouncaging-driven tetrazine ligation will open new avenues for precision medicine.