Optimization of Lipid Nanoparticles for saRNA Expression and Cellular Activation Using a Design-of-Experiment Approach.
Mol Pharm
; 19(6): 1892-1905, 2022 06 06.
Article
in English
| MEDLINE | ID: covidwho-1860276
ABSTRACT
Lipid nanoparticles (LNPs) are the leading technology for RNA delivery, given the success of the Pfizer/BioNTech and Moderna COVID-19 mRNA (mRNA) vaccines, and small interfering RNA (siRNA) therapies (patisiran). However, optimization of LNP process parameters and compositions for larger RNA payloads such as self-amplifying RNA (saRNA), which can have complex secondary structures, have not been carried out. Furthermore, the interactions between process parameters, critical quality attributes (CQAs), and function, such as protein expression and cellular activation, are not well understood. Here, we used two iterations of design of experiments (DoE) (definitive screening design and Box-Behnken design) to optimize saRNA formulations using the leading, FDA-approved ionizable lipids (MC3, ALC-0315, and SM-102). We observed that PEG is required to preserve the CQAs and that saRNA is more challenging to encapsulate and preserve than mRNA. We identified three formulations to minimize cellular activation, maximize cellular activation, or meet a CQA profile while maximizing protein expression. The significant parameters and design of the response surface modeling and multiple response optimization may be useful for designing formulations for a range of applications, such as vaccines or protein replacement therapies, for larger RNA cargoes.
Keywords
Full text:
Available
Collection:
International databases
Database:
MEDLINE
Main subject:
Nanoparticles
/
COVID-19
Topics:
Vaccines
Limits:
Humans
Language:
English
Journal:
Mol Pharm
Journal subject:
Molecular Biology
/
Pharmacy
/
Pharmacology
Year:
2022
Document Type:
Article
Affiliation country:
Acs.molpharmaceut.2c00032
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