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

Abstract 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 H 2 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 H 2 S in pathogens. The consumption of bacterial H 2 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.