Noncovalent complexation of cationic peptides that comprise hydrophilic and hydrophobic domains with RNA provide efficient gene silencing. The hydrophilic domain of positively charged amino acids, such as arginine, lysine, and histidine, provides a net positive charge of at least +8 that condenses the RNA and promotes hydrogen bonding with the anionic cellular membrane to stimulate cellular uptake. The hydrophobic peptide domain of tryptophan and phenylalanine enhances interactions with the lipid bilayer. Terminal modification of the cationic peptides with hydrophobic molecules such as cholesterol, stearic acid, or cholic acid increases the hydrophobicity. The other terminus of the peptide can be modified with hydrophilic molecules such as PEG. These peptides form a micelle-like structure with siRNA and deliver them efficiently to target cells. Protamines are naturally occurring cationic peptides involved in the condensation of chromatin during spermatogenesis. Comprising >65% positively charged arginines, protamines form noncovalent electrostatic complexes with nucleic acids and protect them from enzymatic degradation. Although protamines are intrinsically disordered peptides, in the presence of nucleic acids they switch from a random coil to a structure with one or more α-helices. 340 Protamine-RNA complexes show limited efficacy, possibly due to the tight interaction between the protamine and RNA. 341