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

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

doi:10.1126/sciadv.abc2315

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

Sci Adv. 2020 Aug 21;6(34):eabc2315. doi: 10.1126/sciadv.abc2315. Print 2020 Aug.

Authors

Xinfu Zhang^{1

2}, Weiyu Zhao¹, Giang N Nguyen³, Chengxiang Zhang¹, Chunxi Zeng¹, Jingyue Yan¹, Shi Du¹, Xucheng Hou¹, Wenqing Li¹, Justin Jiang¹, Binbin Deng⁴, David W McComb^{4

5}, Robert Dorkin⁶, Aalok Shah⁶, Luis Barrera⁶, Francine Gregoire⁶, Manmohan Singh⁶, Delai Chen⁷, Denise E Sabatino^{8

9}, Yizhou Dong^{10

11

12

13

14

15}

Affiliations

¹ Division of Pharmaceutics and Pharmacology, College of Pharmacy, The Ohio State University, Columbus, OH 43210, USA.
² State Key Laboratory of Fine Chemicals, Dalian University of Technology, Dalian 116024, China.
³ The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
⁴ Center for Electron Microscopy and Analysis, Department of Materials Science and Engineering, The Ohio State University, Columbus, OH 43210, USA.
⁵ Department of Materials Science and Engineering, The Ohio State University, Columbus, OH 43210, USA.
⁶ Beam Therapeutics, Cambridge, MA 02139, USA.
⁷ Beam Therapeutics, Cambridge, MA 02139, USA. [email protected] [email protected] [email protected].
⁸ The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA. [email protected] [email protected] [email protected].
⁹ Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
¹⁰ Division of Pharmaceutics and Pharmacology, College of Pharmacy, The Ohio State University, Columbus, OH 43210, USA. [email protected] [email protected] [email protected].
¹¹ Department of Biomedical Engineering, The Ohio State University, Columbus, OH 43210, USA.
¹² The Center for Clinical and Translational Science, The Ohio State University, Columbus, OH 43210, USA.
¹³ The Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210, USA.
¹⁴ Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University, Columbus, OH 43210, USA.
¹⁵ Department of Radiation Oncology, The Ohio State University, Columbus, OH 43210, USA.

Abstract

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.

Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Gene Editing
Lipids
Mice
Nanoparticles*
Proprotein Convertase 9*
RNA, Messenger / metabolism

Substances

Lipids
RNA, Messenger
PCSK9 protein, human
Proprotein Convertase 9

Abstract

Publication types

MeSH terms

Substances

Grants and funding