Local mRNA Delivery\nfrom Nanocomposites Made of Gelatin\nand Hydroxyapatite Nanoparticles

Local delivery of messenger ribonucleic acid (mRNA) is\nincreasingly\nbeing advocated as a promising new strategy to enhance the performance\nof biomaterials. While extensive research has been dedicated to the\ncomplexation of these oligonucleotides into nanoparticles to facilitate\nsystemic delivery, research on developing suitable biomaterial carriers\nfor the local delivery of mRNA is still scarce. So far, mRNA-nanoparticles\n(mRNA-NPs) are mainly loaded into traditional polymeric hydrogels.\nHere, we show that calcium phosphate nanoparticles can be used for\nboth reinforcement of nanoparticle-based hydrogels and the complexation\nof mRNA. mRNA was incorporated into lipid-coated calcium phosphate\nnanoparticles (LCPs) formulated with a fusogenic ionizable lipid in\nthe outer layer of the lipid coat. Nanocomposites of gelatin and hydroxyapatite\nnanoparticles were prepared at various ratios. Higher hydroxyapatite\nnanoparticle content increased the viscoelastic properties of the\nnanocomposite but did not affect its self-healing ability. Combination\nof these nanocomposites with peptide, lipid, and the LCP mRNA formulations\nachieved local mRNA release as demonstrated by protein expression\nin cells in contact with the biomaterials. The LCP-based formulation\nwas superior to the other formulations by showing less sensitivity\nto hydroxyapatite and the highest cytocompatibility.