PUBLICATION
Polysarcosine-based lipid formulations for intracranial delivery of mRNA
- Authors
- Bi, D., Unthan, D.M., Hu, L., Bussmann, J., Remaut, K., Barz, M., Zhang, H.
- ID
- ZDB-PUB-230223-45
- Date
- 2023
- Source
- Journal of controlled release : official journal of the Controlled Release Society 356: 1-13 (Journal)
- Registered Authors
- Bi, Dongdong, Bussmann, Jeroen
- Keywords
- Lipid formulations, Polysarcosine, Zebrafish embryo, mRNA intracerebral delivery
- MeSH Terms
-
- Animals
- Lipids
- Liposomes*
- Polyethylene Glycols
- RNA, Messenger
- Sarcosine*
- Tissue Distribution
- Transfection
- Zebrafish
- PubMed
- 36803765 Full text @ J. Control Release
Citation
Bi, D., Unthan, D.M., Hu, L., Bussmann, J., Remaut, K., Barz, M., Zhang, H. (2023) Polysarcosine-based lipid formulations for intracranial delivery of mRNA. Journal of controlled release : official journal of the Controlled Release Society. 356:1-13.
Abstract
Messenger RNA (mRNA) is revolutionizing the future of therapeutics in a variety of diseases, including neurological disorders. Lipid formulations have shown to be an effective platform technology for mRNA delivery and are the basis for the approved mRNA vaccines. In many of these lipid formulations, polyethylene glycol (PEG)-functionalized lipid provides steric stabilization and thus plays a key role in improving the stability both ex vivo and in vivo. However, immune responses towards PEGylated lipids may compromise the use of those lipids in some applications (e.g., induction of antigen specific tolerance), or within sensitive tissues (e.g., central nervous system (CNS)). With respect to this issue, polysarcosine (pSar)-based lipopolymers were investigated as an alternative to PEG-lipid in mRNA lipoplexes for controlled intracerebral protein expression in this study. Four polysarcosine-lipids with defined sarcosine average molecular weight (Mn = 2 k, 5 k) and anchor diacyl chain length (m = 14, 18) were synthesized, and incorporated into cationic liposomes. We found that the content, pSar chain length and carbon tail lengths of pSar-lipids govern the transfection efficiency and biodistribution. Increasing carbon diacyl chain length of pSar-lipid led up to 4- and 6-fold lower protein expression in vitro. When the length of either pSar chain or lipid carbon tail increased, the transfection efficiency decreased while the circulation time was prolonged. mRNA lipoplexes containing 2.5% C14-pSar2k resulted in the highest mRNA translation in the brain of zebrafish embryos through intraventricular injection, while C18-pSar2k-liposomes showed a comparable circulation with DSPE-PEG2k-liposomes after systemic administration. To conclude, pSar-lipid enable efficient mRNA delivery, and can substitute PEG-lipids in lipid formulations for controlled protein expression within the CNS.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping