On-Demand Activatable and Integrated Bioorthogonal Nanocatalyst against Biofilm-Associated Infections.

Bioorthogonal chemistry has emerged as a powerful tool for manipulating biological processes. However, difficulties in controlling the exact location and on-demand catalytic synthesis limit its application in biological systems. Herein, this work constructs an activatable bioorthogonal system integrating a shielded catalyst and prodrug molecules to combat biofilm-associated infections. The catalytic species is activated in response to the hyaluronidase (HAase) secreted by the bacteria and the acidic pH of the biofilm, which is accompanied by the release of prodrugs, to achieve the bioorthogonal catalytic synthesis of antibacterial molecules in situ. Moreover, the system can produce reactive oxygen species (ROS) to disperse bacterial biofilms, enabling the antibacterial molecules to penetrate the biofilm and eliminate the bacteria within it. This study promotes the design of efficient and safe bioorthogonal catalysts and the development of bioorthogonal chemistry-mediated antibacterial strategies.

MOFs Modulate Copper Trafficking in Tumor Cells for Bioorthogonal Therapy.

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.

A Polyoxometalate-Based Pathologically Activated Assay for Efficient Bioorthogonal Catalytic Selective Therapy.

Since polyoxometalates (POMs) can undergo reversible multi-electron redox transformations, they have been used to modulate the electronic environment of metal nanoparticles for catalysis. Besides, POMs possess unique electronic structures and acid-responsive self-assembly ability. These properties inspired us to tackle the drawbacks of the copper-catalyzed azide-alkyne cycloaddition (CuAAC) reaction in biomedical applications, such as low catalytic efficiency and unsatisfactory disease selectivity. Herein, we construct molybdenum (Mo)-based POM nanoclusters doped with Cu (Cu-POM NCs) as a highly efficient bioorthogonal catalyst, which is responsive to pathologicallyacid and H2 S for selective antibiofilm therapy. Leveraging the merits of POMs, the Cu-POM NCs exhibit biofilm-responsive self-assembly behavior, efficient CuAAC-mediated in situ synthesis of antibacterial molecules, and a NIR-II photothermal effect selectively triggered by H2 S in pathogens. The consumption of bacterial H2 S at the pathological site by Cu-POM NCs extremely decreases the number of persisterbacteria, which is conducive to the inhibition of bacterial tolerance and elimination of biofilms. Unlocked at pathological sites and endowed with NIR-II photothermal property, the constructed POM-based bioorthogonal catalytic platform provides new insights into the design of efficient and selective bioorthogonal catalysts for disease therapy.

NIR-II Light Leveraged Dual Drug Synthesis for Orthotopic Combination Therapy.

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.