| Affiliation: | 1. Institute of Organic Chemistry and Biochemistry, Czech Academy Sciences, Flemingovo n. 2, Prague 6, 166 10 Czech Republic Department of Genetics and Microbiology, Charles University and Research Center BIOCEV, Prumyslova 595, Vestec, 252 50 Czech Republic;2. Institute of Organic Chemistry and Biochemistry, Czech Academy Sciences, Flemingovo n. 2, Prague 6, 166 10 Czech Republic;3. Institute of Molecular Genetics, Czech Academy Sciences, Czech Centre for Phenogenomics and Laboratory of Transgenic Models of Diseases, Division BIOCEV, Prumyslova 595, Vestec, 252 50 Czech Republic;4. Laboratory of Structural Biology, Institute of Biology and Medical Genetics, First Faculty of Medicine, Charles University in Prague, Albertov 4, Prague 2, 128 01 Czech Republic |
| Abstract: | Lipid nanoparticles (LNPs) are the most advanced nonviral modality for nucleic acid (NA) delivery, and have recently gained enormous attention in the fields of RNA therapeutics and vaccine development. Here, ionizable adamantane-based lipidoids named XMaNs, which circumvent the usual need for laborious optimization of LNP components for highly diverse types of NAs, are described. The non-toxic XMaN6 lipidoid is highly versatile in entrapment and delivery of siRNA, mRNA, plasmid DNA, and a cyclic dinucleotide. XMaN6-based LNPs efficiently deliver: 1) siRNA into human primary hepatocytes and cell lines that are hard-to-transfect; 2) mRNA into mouse liver; 3) plasmid DNA; 4) 2′,3′-cGAMP into cells and activated the cGAS-STING pathway three orders of magnitude more efficiently than 2′,3′-cGAMP alone. To our knowledge, such universality in delivering different NA types has not been previously described and can accelerate translation of LNPs into the clinic. |
