Zhang, X; Jiang, J; Deng, B; Mccomb, DW; Dorkin, R; Shah, A; Barrera, L; Gregoire, F; Singh, M; Chen, D; Sabatino, DE; Zhao, W; Dong, Y; Nguyen, GN; Zhang, C; Zeng, C; Yan, J; Du, Shi; Hou, X; Li, W; ,
Messenger RNA (mRNA) therapeutics have been explored to treat various genetic disorders. Lipid-derived nanomaterials are currently one of the most promising biomaterials that mediate effective mRNA delivery. However, efficiency and safety of this nanomaterial-based mRNA delivery remains a challenge for clinical applications. Here, we constructed a series of lipid-like nanomaterials (LLNs), named functionalized TT derivatives (FTT), for mRNA-based therapeutic applications in vivo. After screenings on the materials, we identified FTT5 as a lead material for efficient delivery of long mRNAs, such as human factor VIII (hFVIII) mRNA (similar to 4.5 kb) for expression of hFVIII protein in hemophilia A mice. Moreover, FTT5 LLNs demonstrated high percentage of base editing on PCSK9 in vivo at a low dose of base editor mRNA (similar to 5.5 kb) and single guide RNA. Consequently, FTT nanomaterials merit further development for mRNA-based therapy.