9.C.27.  The Nucleic Acid Transmembrane Transporter (NATT) Families

Transmembrane transport of nucleic acids is a key process in cells, which facilitates cell division, gene expression, and even intercellular communication by exchange of genetic information between cells (Li and Schulman 2019). However, the structural features of nucleic acids, including biodegradability, negative charges, and hydrophilic backbones, prevent free diffusion across the cell membranes. (Dowdy 2017).  In fact, it is of biomedical importance to effectively deliver RNA therapeutic agents across cell membranes to exert their intracellular functions. Thanks to the biocompatibility, low immunogenicity, and therapeutic function of nucleic acids (Winkle et al. 2021), several typical delivery techniques based on RNA therapy have been developed to assist in nucleic acid transmembrane transport, such as lipid nanoparticles (LNP) (Mitchell et al. 2021), and polymer‐based nanoparticles (Duncan 2003), viral or bacterial agents (Lundstrom K., Vaccines 2020, 9, 1187), and membrane‐penetrating peptides (Furukawa et al. 2020). In addition, inspired by the way that natural channels transport ions, only a few nucleic acid and protein transport models based on membrane‐spanning nanopores have been reported (Thomsen et al. 2019). Finally, single-stranded nucleic acid transmembrane molecular carriers based on positively charged helical foldamers have been developed (Ge et al. 2024).  None of these systems are natural carriers, and therefore, no amino acid sequences are available for them.