Functionalized lipid-like nanoparticles for in vivo mRNA delivery and base editing.

Zhang, Xinfu; Zhao, Weiyu; Nguyen, Giang N; Zhang, Chengxiang; Zeng, Chunxi; Yan, Jingyue; Du, Shi; Hou, Xucheng; Li, Wenqing; Jiang, Justin; Deng, Binbin; McComb, David W; Dorkin, Robert; Shah, Aalok; Barrera, Luis; Gregoire, Francine; Singh, Manmohan; Chen, Delai; Sabatino, Denise E; Dong, Yizhou

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 (~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 (~5.5 kb) and single guide RNA. Consequently, FTT nanomaterials merit further development for mRNA-based therapy.