NIR-II light-activated and Cu nanocatalyst-enabled bioorthogonal reaction in living systems for efficient tumor therapy

Bioorthogonal reaction refers to chemical reactions that occur within a biological system without interfering the normal biochemical process, offering the unprecedented versatility in engineering chemical reactions within cells. However, the precise regulation of bioorthogonal reaction in living systems is mired by the complexity of the physiological environment and the toxicity of catalysts. Herein, considering the deeper tissue penetration and reduced phototoxicity compared to visible light and ultraviolet, a second near infrared (NIR-II) light-activated Cu-based bioorthogonal reaction is developed to achieve precise spatiotemporal control and effective switching for Cu(I)-catalyzed azide-alkyne cycloaddition (CuAAC) mediated chemical transformations in tumor, reducing the off-target effects. The catalytic activity of Cu catalyst through valence state interconversion between Cu(II) and Cu(I) can be precisely regulated in a reversible manner under NIR-II light irradiation-induced photoelectron transfer, which controls the extent of desired drug synthesis in bioorthogonal reaction. Meanwhile, the adverse effects of Cu(I) can be substantially mitigated within normal tissues due to their oxygen-rich condition. By utilizing NIR-II light and oxygen level, the Cu bioorthogonal catalyst achieves a balance between catalytic activity and biocompatibility. The ability to achieve precise spatiotemporal control and reversible catalysis makes this NIR-II light-mediated CuAAC platform an efficient and adaptable tool for bioorthogonal chemistry in living systems.