@article{01JTNCMEJAKFNARN6QJQBG72PP,
  abstract     = {{Self-amplifying mRNA (saRNA) is witnessing increased interest as a platform technology for protein replacement therapy, gene editing, immunotherapy, and vaccination. saRNA can replicate itself inside cells, leading to a higher and more sustained production of the desired protein at a lower dose. Controlling innate immune activation, however, is crucial to suppress unwanted inflammation upon delivery and self-replication of RNA in vivo. In this study, we report on a class of beta-aminoester lipids (beta AELs) synthesized through the Michael addition of an acrylate to diethanolamine, followed by esterification with fatty acids. These lipids possessed one or two ionizable amines, depending on the use of nonionic or amine-containing acrylates. We utilized beta AELs for encapsulating saRNA in lipid nanoparticles (LNPs) and evaluated their transfection efficiency in vitro and in vivo in mice, while comparing them to LNPs containing ALC-0315 as an ionizable lipid reference. Among the tested lipids, OC7, which comprises two unsaturated oleoyl alkyl chains and an ionizable azepanyl motif, emerged as a beta AEL with low cytotoxicity and immunogenicity relative to ALC-0315. Interestingly, saRNA delivered via the OC7 LNP exhibited a distinct in vivo transfection profile. Initially, intramuscular injection of OC7 LNP resulted in low protein expression shortly after administration, followed by a gradual increase over a period of up to 7 days. This pattern is indicative of successful self-amplification of saRNA. In contrast, saRNA delivered via ALC-0315 LNP demonstrated high protein translation initially, which gradually declined over time and lacked the amplification seen with OC7 LNP. We observed that, in contrast to saRNA OC7 LNP, saRNA ALC-0315 LNP induced potent innate immune activation by triggering cytoplasmic RIG-I-like receptors (RLRs), likely due to the highly efficient endosomal membrane rupturing properties of ALC-0315 LNP. Consequently, the massive production of type I interferons quickly hindered the amplification of the saRNA. Our findings highlight the critical role of the choice of ionizable lipid for saRNA formulation in LNPs, particularly in shaping the qualitative profile of protein expression. For applications where minimizing inflammation is desired, the use of ionizable lipids, such as the beta AEL reported in this study, that elicit a low type I interferon response in saRNA LNP is crucial.}},
  author       = {{De Lombaerde, Emily and Cui, Xiaole and Chen, Yong and Zhong, Zifu and Deckers, Julie and Mencarelli, Giulia and Opsomer, Lisa and Wang, Haixiu and De Baere, Jamie and Lienenklaus, Stefan and Lambrecht, Bart and Sanders, Niek and De Geest, Bruno}},
  issn         = {{1936-0851}},
  journal      = {{ACS NANO}},
  keywords     = {{lipid nanoparticles,mRNA,self-amplifying,innate immune activation,ionizable lipids,IMMUNOGENICITY,VACCINES,IMPACT,SIRNA}},
  language     = {{eng}},
  number       = {{41}},
  pages        = {{28311--28324}},
  title        = {{Amplification of protein expression by self-amplifying mRNA delivered in lipid nanoparticles containing a β-aminoester ionizable lipid correlates with reduced innate immune activation}},
  url          = {{http://doi.org/10.1021/acsnano.4c09677}},
  volume       = {{18}},
  year         = {{2024}},
}

Altmetric

View in Altmetric

Web of Science

Times cited: