TY - JOUR
T1 - Optimization of the activity and biodegradability of ionizable lipids for mRNA delivery via directed chemical evolution
AU - Han, Xuexiang
AU - Alameh, Mohamad Gabriel
AU - Xu, Ying
AU - Palanki, Rohan
AU - El-Mayta, Rakan
AU - Dwivedi, Garima
AU - Swingle, Kelsey L.
AU - Xu, Junchao
AU - Gong, Ningqiang
AU - Xue, Lulu
AU - Shi, Qiangqiang
AU - Yoon, Il Chul
AU - Warzecha, Claude C.
AU - Wilson, James M.
AU - Weissman, Drew
AU - Mitchell, Michael J.
N1 - Publisher Copyright:
© The Author(s), under exclusive licence to Springer Nature Limited 2024.
PY - 2024/11
Y1 - 2024/11
N2 - Ionizable lipids largely determine the biocompatibility of lipid nanoparticles (LNPs) and the efficacy for mRNA delivery. Rational design and combinatorial synthesis have led to the development of potent and biodegradable ionizable lipids, yet methodologies for the stepwise optimization of ionizable lipid structure are lacking. Here we show that iterative chemical derivatization and combinatorial chemistry, and in particular the amine–aldehyde–alkyne coupling reaction, can be leveraged to iteratively accelerate the structural optimization of propargylamine-based ionizable lipids (named A3-lipids) to improve their delivery activity and biodegradability. Through five cycles of such directed chemical evolution, we identified dozens of biodegradable and asymmetric A3-lipids with delivery activity comparable to or better than a benchmark ionizable lipid. We then derived structure−activity relationships for the headgroup, ester linkage and tail. Compared with standard ionizable lipids, the lead A3-lipid improved the hepatic delivery of an mRNA-based genome editor and the intramuscular delivery of an mRNA vaccine against SARS-CoV-2. Structural criteria for ionizable lipids discovered via directed chemical evolution may accelerate the development of LNPs for mRNA delivery.
AB - Ionizable lipids largely determine the biocompatibility of lipid nanoparticles (LNPs) and the efficacy for mRNA delivery. Rational design and combinatorial synthesis have led to the development of potent and biodegradable ionizable lipids, yet methodologies for the stepwise optimization of ionizable lipid structure are lacking. Here we show that iterative chemical derivatization and combinatorial chemistry, and in particular the amine–aldehyde–alkyne coupling reaction, can be leveraged to iteratively accelerate the structural optimization of propargylamine-based ionizable lipids (named A3-lipids) to improve their delivery activity and biodegradability. Through five cycles of such directed chemical evolution, we identified dozens of biodegradable and asymmetric A3-lipids with delivery activity comparable to or better than a benchmark ionizable lipid. We then derived structure−activity relationships for the headgroup, ester linkage and tail. Compared with standard ionizable lipids, the lead A3-lipid improved the hepatic delivery of an mRNA-based genome editor and the intramuscular delivery of an mRNA vaccine against SARS-CoV-2. Structural criteria for ionizable lipids discovered via directed chemical evolution may accelerate the development of LNPs for mRNA delivery.
UR - https://www.scopus.com/pages/publications/85209752486
U2 - 10.1038/s41551-024-01267-7
DO - 10.1038/s41551-024-01267-7
M3 - 文章
C2 - 39578640
AN - SCOPUS:85209752486
SN - 2157-846X
VL - 8
SP - 1412
EP - 1424
JO - Nature Biomedical Engineering
JF - Nature Biomedical Engineering
IS - 11
ER -
