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

• Published in: Science advances Vol. 6; no. 34
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: United States American Association for the Advancement of Science 01.08.2020
• Subjects: Animals; Gene Editing; Life Sciences; Lipids; Materials Science; Mice; Nanoparticles; Proprotein Convertase 9; RNA, Messenger - metabolism; SciAdv r-articles
• ISSN: 2375-2548; 2375-2548
• DOI: 10.1126/sciadv.abc2315

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.