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Metal-coordination-directed biomolecule crosslinking in nature has been used for synthesizing various biopolymers, including DNA, peptides, proteins, and polysaccharides. However, the RNA biopolymer has been avoided so far, as due to the poor stability of the RNA molecules, the formation of a biopolymer may alter the biological function of the molecules. Herein, for the first time, we report Zn2+ -driven RNA self-assembly forming spherical nanoparticles while retaining the integrity and biological function of RNA. Various functional RNAs of different compositions, shapes, and lengths from 20 to nearly 1000 nucleotides were used, highlighting the versatility of this approach. The assembled nanospheres possess a superior RNA-loading efficiency, pharmacokinetics, and bioavailability. In-vitro and in-vivo evaluation demonstrated mRNA delivery for expressing GFP proteins, and microRNA delivery to triple-negative breast cancer. This coordination-directed self-assembly behavior amplifies the horizons of RNA coordination chemistry and the application scope of RNA-based therapeutics.

Metal-coordination-directed biomolecule crosslinking in nature has been used for synthesizing various biopolymers, including DNA, peptides, proteins, and polysaccharides. However, the RNA biopolymer has been avoided so far, as due to the poor stability of the RNA molecules, the formation of a biopolymer may alter the biological function of the molecules. Herein, for the first time, we report Zn