Photodynamic activity rather than drilling causes membrane damage by a light-powered molecular nanomotor

• Published in: Journal of photochemistry and photobiology. B, Biology Biology, 2023-02, Vol.239, p.112633-112633, Article 112633
• Main Authors: Firsov, Alexander M., Pfeffermann, Juergen, Benditkis, Anton S., Rokitskaya, Tatyana I., Kozlov, Anton S., Kotova, Elena A., Krasnovsky, Alexander A., Pohl, Peter, Antonenko, Yuri N.
• Format: Article
• Language: English
• Subjects: Artificial molecular motors; Cell Membrane; Gramicidin - chemistry; Gramicidin - pharmacology; Lipid Bilayers - chemistry; Lipid peroxidation; Nanomotor; Photodynamic; Photosensitizer; Singlet oxygen; Singlet Oxygen - chemistry; Unilamellar Liposomes
• ISSN: 1011-1344; 1873-2682
• DOI: 10.1016/j.jphotobiol.2022.112633

The chase toward endowing chemical compounds with machine-like functions mimicking those of biological molecular machineries has yielded a variety of artificial molecular motors (AMMs). Pharmaceutical applications of photoexcited monomolecular unidirectionally-rotating AMMs have been envisioned in view of their ability to permeabilize biological membranes. Nonetheless, the mechanical properties of lipid membranes render the proposed drilling activity of AMMs doubtful. Here, we show that singlet oxygen released by a photoexcited “molecular drill” oxidized unsaturated lipids composing giant unilamellar vesicles. In contrast, giant liposomes built of saturated lipids were inert to AMM photoactuation. The AMM did not mechanically destroy gramicidin A ion channels in planar bilayer lipid membranes but instead photoinactivated them. Sodium azide, a singlet oxygen quencher, reduced both AMM-mediated light-induced dye release from unsaturated large unilamellar vesicles and protected gramicidin A from photoinactivation. Upon additional consideration of the underlying bilayer mechanics, we conclude that AMMs' envisioned therapeutic and pharmaceutical applications rely on their photodynamic activity rather than their nanomechanical drilling abilities. •Claims about drilling lipid bilayers by light-powered motors violate the laws of membrane elasticity.•Testing one of these “drilling” molecular motors, M3, we found singlet oxygen phosphorescence.•M3-induced photooxidation permeabilizes vesicles made of unsaturated but not saturated lipids.•Inhibitors of photooxidation protect the membrane barrier from “drilling” by M3.•Singlet oxygen scavengers suppress M3-sensitized gramicidin channel photoinactivation.