Emergence of a Cell-Guided Multivalent Ligand of Enzymes on Cancer Cells Triggered by Click Reaction between Hetero Nanoassemblies

Stimuli-responsive nanomaterials with multivalent ligands have attracted significant attention in the context of cancer chemotherapy and imaging. However, challenges remain such as nonselective stimuli response and/or existence of triggers in healthy regions in addition to the intrinsic heterogeneity of cancer that causes insufficient target recognition. Inspired by the expression of precise and diverse functions of biological machineries triggered by specific protein–protein complexation and conformational change, we report an artificial system where a bio-orthogonal click reaction between hetero nanoassemblies triggers their complexation and conformational changes, resulting in the emergence of multivalent ligands for cancer-associated enzymes, namely, carbonic anhydrase IX (CAIX). We also demonstrated that the multivalent ligands selectively inhibited the proliferation of cancer cells overexpressing CAIX under hypoxic conditions. Additionally, the click reaction between nanoassemblies in the presence of target cells provided higher efficacy of the emerged multivalent ligands than that pre-formed in the absence of cells. Our study provides a basis for the development of multivalent ligands displaying adaptive binding interfaces for target cancer cells with high selectivity and affinity to thus potentially overcome tumor heterogeneity.