Nontoxic mRNA vehicles based on electrically neutral self-assembling peptides

Abstract

The cationic molecules and low-molecular-weight amphiphiles commonly used in nonviral gene delivery vehicles often induce adverse nonspecific effects, notably cytotoxicity and detergent-like unfavourable membrane activity. To address these limitations, here we report the development of a nontoxic mRNA-condensing agent based on electrically neutral self-assembling peptides (ENSPs). Driven by cooperative hydrogen bonding and hydrophobic interactions, ENSPs coassemble with mRNA into discrete nanotube-shaped complexes. ENSP-based mRNA vehicles are almost nontoxic to mammalian cells and exhibit negligible detergent-like membrane activity toward red blood cells both in vitro and in vivo, unlike conventional delivery vehicles. The lower toxicity of the electrically neutral, peptide-based mRNA-condensing agents represents a potentially safer delivery option compared to current standard methods. Cationic and amphiphilic molecules often used in gene delivery can have toxic side effects. Here, the authors report on the co-assembly of electrically neutral self-assembling peptides and mRNA which produces highly biocompatible, nanotubular delivery vehicles with lower potential toxicity.