@article{01J05WZK97DHG6BTBDJB738B0B,
  abstract     = {{Messenger RNA (mRNA) has emerged as a promising therapeutic modality for various diseases. However, efficient delivery of mRNA into target cells remains a significant challenge. In this study, the combinatorial synthesis and characterization of a novel series of ionizable biscarbamate lipids (IBLs) for mRNA lipid nanoparticle (LNP) delivery are reported. A simplified and scalable method is developed, resulting in IBLs suitable for formulating mRNA into stable LNPs. Two generations of IBLs are synthesized and evaluated for their mRNA transfection capacity in vitro, using eGFP as a reporter protein, leading to the identification of S-Ac7-DOG as a lead IBL. Upon intramuscular vaccination, S-Ac7-DOG LNPs instigated robust antigen-specific CD8+ T cell responses against an mRNA encoded viral oncoprotein and a tumor neo-antigen. In comparison to MC3 LNPs, which are used as a benchmark, S-Ac7-DOG LNPs exhibit low reactogenicity, robust mRNA transfection, and a distinct biodistribution, with higher accumulation in draining lymph nodes and spleen. These findings highlight the potential of IBLs as a novel and promising class of ionizable lipids for mRNA delivery in vaccines and beyond.

This study reports on combinatorial synthesis of ionizable biscarbamate lipids (IBLs) for mRNA lipid nanoparticle (LNP) delivery. In vitro screenings identify S-Ac7-DOG as a lead IBL, with high mRNA transfection capacity. In vivo, S-Ac7-DOG mRNA LNPs combine low reactogenicity with high local transfection. S-Ac7-DOG LNPs encapsulating mRNA encoding for tumor antigen can mount protective T cell responses against a tumor challenge. image}},
  articleno    = {{2310623}},
  author       = {{De Lombaerde, Emily and Chen, Yong and Ye, Tingting and Deckers, Julie and Mencarelli, Giulia and Deswarte, Kim and Lauwers, Heleen and De Coen, Ruben and Kasmi, Sabah and Bevers, Sanne and Kuchmiy, Anna and Bogaert, Bram and Baekens, Lies and Zhong, Zifu and Lamoot, Alexander and Sanders, Niek and Lambrecht, Bart and Pires da Silva Baptista, Antonio and De Koker, Stefaan and De Geest, Bruno}},
  issn         = {{1616-301X}},
  journal      = {{ADVANCED FUNCTIONAL MATERIALS}},
  keywords     = {{immune-therapyionizable lipids,lipid nanoparticles,mRNAvaccines,immune-therapy,ionizable lipids,mRNA,vaccines}},
  language     = {{eng}},
  number       = {{21}},
  pages        = {{2310623:1--2310623:16}},
  title        = {{Combinatorial screening of biscarbamate ionizable lipids identifies a low reactogenicity lipid for lipid nanoparticle mRNA delivery}},
  url          = {{http://doi.org/10.1002/adfm.202310623}},
  volume       = {{34}},
  year         = {{2024}},
}

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