Zn²⁺‐Coordination‐Driven RNA Assembly with Retained Integrity and Biological Functions

Abstract

Metal-coordination-directed biomolecule crosslinking in nature has been used for synthesizing various biopolymers,including DNA, peptides,proteins,and polysaccharides. However,the RNAbiopolymer has been avoided so far,asdue to the poor stability of the RNAm olecules,t he formation of ab iopolymer may alter the biological function of the molecules.H erein, for the first time,w er eport Zn 2+ -driven RNAs elf-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 as uperior RNA-loading efficiency,p harmacokinetics, and bioavailability.I n-vitro and in-vivo evaluation demonstrated mRNAd elivery for expressing GFP proteins,a nd microRNAd elivery to triple-negative breast cancer.T his coordination-directed self-assembly behavior amplifies the horizons of RNAc oordination chemistry and the application scope of RNA-based therapeutics.

Aptamer-Functionalized ZIF-8 Nanomedicine for Targeted Delivery of Gefitinib and siRNA to Treat Tyrosine-Kinase-Inhibitor-Resistant Nonsmall-Cell Lung Cancer

“…It has been reported that the imidazole- and pyridine-type nitrogens of nucleotides in RNA were well suited for Zn 2+ binding. The phosphate unit and keto oxygen also have high affinity toward Zn 2+ to form chelate cross-links. , Therefore, we speculated that the competition between siRNA and 2-dimethylimidazole to coordinate with Zn 2+ ions decreased the efficiency of ZIF-8 crystal formation, thereby reducing the size of the NPs. These results indicated that the encapsulation of siRNA had a significant influence on the crystal structure of ZIF-8 NPs.…”

Nanoformulations targeting immune cells for cancer therapy: mRNA therapeutics

“…Other candidates that are at the early stage in mRNA delivery potentially offer new opportunities in cancer immunotherapy, mainly including mesoporous silica nanoparticles with a high porosity [ 89 ], Zn 2+ ions [ 125 ], outer membrane vesicles (OMVs) derived from bacteria [ 24 ]. The advantages and disadvantages of representative types of mRNA delivery nanoparticles are summarized in Table 1 .…”

Cellular Trafficking of Nanotechnology‐Mediated mRNA Delivery

“…[11] To avoid these cationrelated side effects, non-electrostatic loading strategies driven by other interactions like base complementary pairing, [84][85][86] hydrogen bonding, [87] and coordination have been explored for mRNA delivery. [88,89] For example, forming metal/mRNA complex via metal coordination-mediated self-assembly is a practical strategy to condense mRNA. Zou et al applied Zn 2+ -directed mRNA selfassembly to prepare spherical NPs, which preserved the biological function of mRNA and achieved effective green fluorescent protein (GFP) expression, demonstrating the potential of metal coordination-driven mRNA self-assembly and broaden the application of mRNA-based therapeutics.…”

“…Zou et al applied Zn 2+ -directed mRNA selfassembly to prepare spherical NPs, which preserved the biological function of mRNA and achieved effective green fluorescent protein (GFP) expression, demonstrating the potential of metal coordination-driven mRNA self-assembly and broaden the application of mRNA-based therapeutics. [88] Various types of mRNA delivery systems have been developed, including lipid-based, polymer-based, nucleic acid-based, peptide-based, protein-based, cell-based, biological membranebased, and hybrid delivery systems (Figure 4). Of note, apart from mRNA itself, the mRNA delivery system also has impacts on the immunogenicity and inflammation of the final mRNA nanomedicines.…”