Functionalized lipid-like nanoparticles for in vivo mRNA delivery and base editing PMID: 32937374

ADC Targets in Oncology

2026-04-10

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

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.