Combinatorial design of nanoparticles for pulmonary mRNA delivery and genome editing

Bowen Li; Rajith Singh Manan; Shun-Qing Liang; Akiva Gordon; Allen Jiang; Andrew Varley; Guangping Gao; Robert Langer; Wen Xue; Daniel Anderson

doi:10.1038/s41587-023-01679-x

Combinatorial design of nanoparticles for pulmonary mRNA delivery and genome editing

Nat Biotechnol. 2023 Oct;41(10):1410-1415. doi: 10.1038/s41587-023-01679-x. Epub 2023 Mar 30.

Authors

Bowen Li^#^{1

2

3

4}, Rajith Singh Manan^#^{1

2}, Shun-Qing Liang^#⁵, Akiva Gordon^{1

2}, Allen Jiang^{1

2}, Andrew Varley³, Guangping Gao^{5

6}, Robert Langer^{1

2

7

8

9}, Wen Xue^{10

11}, Daniel Anderson^{12

13

14

15

16}

Affiliations

¹ David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA.
² Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA.
³ Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Ontario, Canada.
⁴ Institute of Biomedical Engineering, University of Toronto, Toronto, Ontario, Canada.
⁵ RNA Therapeutics Institute, University of Massachusetts Medical School, Worcester, MA, USA.
⁶ Horae Gene Therapy Center and Department of Microbiology and Physiological Systems, University of Massachusetts Medical School, Worcester, MA, USA.
⁷ Department of Anesthesiology, Boston Children's Hospital, Boston, MA, USA.
⁸ Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, MA, USA.
⁹ Harvard-MIT Division of Health Science and Technology, Massachusetts Institute of Technology, Cambridge, MA, USA.
¹⁰ RNA Therapeutics Institute, University of Massachusetts Medical School, Worcester, MA, USA. [email protected].
¹¹ Li Weibo Institute for Rare Diseases Research, University of Massachusetts Medical School, Worcester, MA, USA. [email protected].
¹² David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA. [email protected].
¹³ Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA. [email protected].
¹⁴ Department of Anesthesiology, Boston Children's Hospital, Boston, MA, USA. [email protected].
¹⁵ Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, MA, USA. [email protected].
¹⁶ Harvard-MIT Division of Health Science and Technology, Massachusetts Institute of Technology, Cambridge, MA, USA. [email protected].

^# Contributed equally.

Abstract

The expanding applications of nonviral genomic medicines in the lung remain restricted by delivery challenges. Here, leveraging a high-throughput platform, we synthesize and screen a combinatorial library of biodegradable ionizable lipids to build inhalable delivery vehicles for messenger RNA and CRISPR-Cas9 gene editors. Lead lipid nanoparticles are amenable for repeated intratracheal dosing and could achieve efficient gene editing in lung epithelium, providing avenues for gene therapy of congenital lung diseases.

MeSH terms

Animals
CRISPR-Cas Systems*
Gene Editing* / methods
Gene Transfer Techniques
Genetic Therapy / methods
Humans
Lipids / chemistry
Lung* / metabolism
Mice
Nanoparticles* / chemistry
RNA, Messenger* / genetics

Substances

RNA, Messenger
Lipids

Abstract

MeSH terms

Substances

Grants and funding