Designing Nuclease‐Resistant Enzyme‐Mimicking Assemblies of Oligonucleotides Through Supramolecular Conjugation with Platinum(II) Complexes

Abstract

Abstract The utility of oligonucleotides has evolved beyond merely delivering genetic information to playing a transformative role in functional nanotechnology. Specifically, the enzyme‐like properties of catalytic oligonucleotides, including ribozyme, DNAzyme, and their mimics, offer unique opportunities in bioengineering. A primary challenge in leveraging these catalytic oligonucleotide structures in biomedical applications is their susceptibility to degradation by nucleases. Herein, we introduce a high‐affinity (10 7  M −1 ) salt‐bridge interaction‐mediated generalized noncovalent fabrication strategy to construct arrays of oligonucleotide‐templated metal complexes, producing catalytically active hierarchical assemblies displaying resistance to nucleases in human serum. The one‐dimensional isodesmic polymeric growth of the supramolecular structures between oligonucleotides and guanidinium containing Pt(II)‐complex generates Pt ··· Pt interactions imparting luminescence enhancement (8–10 fold) with long‐lived (∼30 ns) excited states. Consequently, light‐mediated singlet oxygen generation enables efficient catalytic oxidation of substrates. Notably, the catalytic activity exclusively resembles oxidases, which function in the absence of H 2 O 2 (an essential component of peroxidases), unlike conventional nucleotide‐based enzyme mimics. The assembly showcases light‐dependent anticancer activity in vitro, with excellent biocompatibility. Overall, the ease of production and robustness of functional oligonucleotide‐based higher‐order materials, coupled with on‐demand photoactivation of exclusive oxidase enzyme‐like activity, makes the new supramolecular platform a promising candidate for practical biomedical applications.