Intracellular Delivery via Noncharged Sequence-Defined Cell-Penetrating Oligomers

Intracellular drug delivery systems are often limited by their poor serum stability and delivery efficiency. Cell-penetrating peptides (CPPs), particularly those derived from basic protein subunits, have been studied extensively in this regard and used for the delivery of a variety of cargoes in vitro. Although promising, traditional cationic CPPs have some drawbacks that hinder their therapeutic application such as rapid proteolytic degradation and undesired interactions with the biological milieu. To overcome these limitations, this article details the discovery of a new class of noncharged cell-penetrating oligoTEAs (CPOTs) that undergo extensive and rapid cellular entry across different cell lines with low cytotoxicity. CPOTs outperform a widely used CPP, R9 peptide. This new class of highly efficient noncharged macromolecular transporters are distinct from their cationic counterparts and show strong promise for the intracellular delivery of hydrophilic small-molecule therapeutics.