Development of a Light-Triggered Biotin-Bioorthogonal System for Targeted Anti-Tumor Therapy

Abstract Recently, bioorthogonal reactions have been widely applied in drug delivery. However, conventional bioorthogonal reactions, such as the uncontrollable coupling between tetrazine (TZ) and trans-cyclooctene (TCO), lack effective control. To address this, we designed a light-triggered bioorthogonal system, enabling spatiotemporal control. Upon 2 min irradiation with a blue LED (20 W), T-2B was fully released from T-1B. It subsequently reacted with TCO-conjugated probes (TCO-Cy5.5) and prodrugs (TCO–DOX), enabling bioimaging and active drug release (DOX). Meanwhile, TCO–DOX exhibited greater cell permeability, leading to consistently higher intracellular concentrations both in vitro and in vivo post-TZ reactions. This strategy presents a promising approach to circumvent the existing efficacy and toxicity limitations of DOX-mediated chemoimmunotherapy. Consequently, the tumor-specific accumulation of DOX potently inhibited cell proliferation and potentiated tumor immune response in both cellular and animal models. Collectively, this work presents a feasible and effective therapeutic regimen.