21:T449,Pd-catalyzed bioorthogonal bond cleavage reactions are widely used and frequently reported. It is circumscribed by low reaction efficiency, which may encumber the therapeutic outcome when applied to physiological environments. Herein, an NIR-II light promoted integrated catalyst (CuS@PDA/Pd) (PDA - polydopamine) is designed to accelerate the reaction efficiency and achieve a dual bioorthogonal reaction for combination therapy. As NIR-II light can penetrate deeply into tissue, the Pd-mediated cleavage reaction can be promoted both in vitro and in vivo by the photothermal properties of CuS, beneficial to orthotopic 4T1 tumor treatment. In addition, CuS also catalyzes the synthesis of active resveratrol analogs by the CuAAC reaction. These simultaneously produced anticancer agents result in enhanced antitumor cytotoxicity in comparison to the single treatments. This is a fascinating study to devise an integrated catalyst boosted by NIR-II light for dual bioorthogonal catalysis, which may provide the impetus for efficient bioorthogonal combination therapy in vivo.22:T46c,In situ drug synthesis using the copper-catalyzed azide-alkyne cycloaddition (CuAAC) reaction has attracted considerable attention in tumor therapy because of its satisfactory effectiveness and reduced side-effects. However, the exogenous addition of copper catalysts can cause cytotoxicity and has hampered biomedical applications in vivo. Here, we design and synthesize a metal-organic framework (MOF) to mimic copper chaperone, which can selectively modulate copper trafficking for bioorthogonal synthesis with no need of exogenous addition of copper catalysts. Like copper chaperones, the prepared ZIF-8 copper chaperone mimics specifically bind copper ions through the formation of coordination bonds. Moreover, the copper is unloaded under the acidic environment due to the dissipation of the coordination interactions between metal ions and ligands. In this way, the cancer cell-targeted copper chaperone mimics can selectively transport copper ions into cells. Regulation of intracellular copper trafficking may inspire constructing bioorthogonal catalysis system with reduced metal cytotoxicity in live cells.

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