An Orthogonal Array Optimization of Lipid-like Nanoparticles for mRNA Delivery in Vivo

Bin Li; Xiao Luo; Binbin Deng; Junfeng Wang; David W McComb; Yimin Shi; Karin M L Gaensler; Xu Tan; Amy L Dunn; Bryce A Kerlin; Yizhou Dong

doi:10.1021/acs.nanolett.5b03528

An Orthogonal Array Optimization of Lipid-like Nanoparticles for mRNA Delivery in Vivo

Nano Lett. 2015 Dec 9;15(12):8099-107. doi: 10.1021/acs.nanolett.5b03528. Epub 2015 Nov 6.

Authors

Bin Li¹, Xiao Luo¹, Binbin Deng², Junfeng Wang¹, David W McComb², Yimin Shi³, Karin M L Gaensler³, Xu Tan⁴, Amy L Dunn^{5

6}, Bryce A Kerlin^{5

6

7}, Yizhou Dong¹

Affiliations

¹ Division of Pharmaceutics and Pharmaceutical Chemistry, College of Pharmacy, The Ohio State University , Columbus, Ohio 43210, United States.
² Center for Electron Microscopy and Analysis, Department of Materials Science and Engineering, The Ohio State University , Columbus, Ohio 43212, United States.
³ Department of Medicine, University of California-San Francisco , San Francisco, California 94143, United States.
⁴ Tsinghua-Peking Center for Life Sciences, School of Medicine, Tsinghua University , Beijing 100084, China.
⁵ Division of Hematology/Oncology/BMT, Nationwide Children's Hospital , Columbus, Ohio 43205, United States.
⁶ Department of Pediatrics, College of Medicine, The Ohio State University , Columbus, Ohio 43205, United States.
⁷ Center for Clinical and Translational Research, The Research Institute at Nationwide Children's Hospital , Columbus, Ohio 43205, United States.

Abstract

Systemic delivery of mRNA-based therapeutics remains a challenging issue for preclinical and clinical studies. Here, we describe new lipid-like nanoparticles (TT-LLNs) developed through an orthogonal array design, which demonstrates improved delivery efficiency of mRNA encoding luciferase in vitro by over 350-fold with significantly reduced experimental workload. One optimized TT3 LLN, termed O-TT3 LLNs, was able to restore the human factor IX (hFIX) level to normal physiological values in FIX-knockout mice. Consequently, these mRNA based nanomaterials merit further development for therapeutic applications.

Keywords: Lipid-like nanoparticles; genetic disorders; hemophilia; mRNA delivery; orthogonal array design.

Publication types

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

MeSH terms

Humans
Lipids / chemistry*
Nanoparticles*
RNA, Messenger / administration & dosage*

Substances

Lipids
RNA, Messenger

Abstract

Publication types

MeSH terms

Substances

Grants and funding