Passive water-lipid peptide translocators with conformational switches: from single-molecule probe to cellular assay

Peptide design for unassisted passive water-lipid translocation remains a challenge, notwithstanding its importance for drug delivery. We introduce a design paradigm based on conformational switches operating as passive translocation vehicles. The interfacial behavior of the molecular prototype, probed in single-molecule AFM experiments, reveals a near-barrierless translocation. The associated free-energy agrees with mesoscopic measurements, and the in vitro behavior is quantitatively reproduced in cellular assays. The prototypes herald the advent of novel nanobiomaterials for passive translocation.