Water-soluble Cu₃₀ nanoclusters as a click chemistry catalyst for living cell labeling via azide-alkyne cycloaddition

Cu(I)-catalyzed azide-alkyne cycloadditions (CuAAC) have gained increasing interest in the selective labeling of living cells and organisms with biomolecules. However, their application is constrained either by the high cytotoxicity of Cu(I) ions or the low activity of CuAAC in the internal space of living cells. This paper reports the design of a novel Cu-based nanocatalyst, water-soluble thiolated Cu₃₀ nanoclusters (NCs), for living cell labeling via CuAAC. The Cu₃₀ NCs offer good biocompatibility, excellent stability, and scalable synthesis (e.g., gram scale), which would facilitate potential commercial applications. By combining the highly localized Cu(I) active species on the NC surface and good structural stability, the Cu₃₀ NCs exhibit superior catalytic activities for a series of Huisgen cycloaddition reactions with good recyclability. More importantly, the biocompatibility of the Cu₃₀ NCs enables them to be a good catalyst for CuAAC, whereby the challenging labeling of living cells can be achieved via CuAAC on the cell membrane. This study sheds light on the facile synthesis of atomically precise Cu NCs, as well as the design of novel Cu NCs-based nanocatalysts for CuAAC in intracellular bioorthogonal applications.