2. Academic Validation
  3. Functionalized lipid-like nanoparticles for in vivo mRNA delivery and base editing

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.
Xinfu Zhang 1 2,  Weiyu Zhao 1,  Giang N Nguyen 3,  Chengxiang Zhang 1,  Chunxi Zeng 1,  Jingyue Yan 1,  Shi Du 1,  Xucheng Hou 1,  Wenqing Li 1,  Justin Jiang 1,  Binbin Deng 4,  David W McComb 4 5,  Robert Dorkin 6,  Aalok Shah 6,  Luis Barrera 6,  Francine Gregoire 6,  Manmohan Singh 6,  Delai Chen 7,  Denise E Sabatino 8 9,  Yizhou Dong 10 11 12 13 14 15
Affiliations

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. dong.525@osu.edu dsabatin@pennmedicine.upenn.edu dchen@beamtx.com.
  • 8 The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA. dong.525@osu.edu dsabatin@pennmedicine.upenn.edu dchen@beamtx.com.
  • 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. dong.525@osu.edu dsabatin@pennmedicine.upenn.edu dchen@beamtx.com.
  • 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.
PMID: 32937374 DOI: 10.1126/sciadv.abc2315
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.

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