The imidazole group of histidine (His) can absorb protons in the acidic environment of the endosome, leading to osmotic swelling, membrane disruption and eventually nucleic acid escape. Accordingly, Lo et al. [183] modified Tat, which can bind and condense DNA through ionic interactions but has no acidic residues that can promote endosomal release, with different numbers of His residues. Highest reporter gene expression could be achieved after plasmid delivery with a Tat peptide covalently fused to 10 His residues (Tat-10H). Insertion of two additional cysteine residues into Tat-10H further enhanced stability of peptide/DNA complexes and transgene expression through formation of interpeptide disulfide bonds. Youngblood et al. [184] evaluated the influence of the stability of arginine-rich peptide PMO conjugates on cellular uptake and antisense activity. They could show that the stability is affected by the amino acid composition and the type of linkage to the cargo. Moreover, they found that degraded fragments could not escape anymore from endosomal or lysosomal compartments.