Two-Photon Responsive Amphiphilic Photoswitches as Molecular Modulators of Lipid Order and Curvature

Molecular photoswitches capable of controlling membrane properties under light stimulation represent promising tools for manipulating biomimetic and biological interfaces. We report the synthesis and photophysical characterization of amphiphilic P-type photoswitches exhibiting efficient and reversible E↔Z photoisomerization under both one-photon (1PA: 375/300 nm) and two-photon (2PA: 750/630 nm) excitation. Their incorporation into DPPC monolayers and bilayers enables light-driven modulation of membrane structure. Short-chain analogues (C4 derivatives) remain well-mixed with DPPC and promote curvature upon E↔Z photoisomerization, regardless of the polarity of their headgroup (hydroxyl, OH or hexaethylenglycol, HEG). In contrast, long-chain derivatives (C12) behave either as light-activated compressants or expanders, depending on the strength their headgroup interactions. The HEG-terminated C12 photoswitch (Sw-HEG–C12) favors anchoring at the interface and induces lateral demixing (microsegregation) and domain stiffening, leading to a decrease in surface pressure in DPPC monolayers and an increase in vesicle size upon E→Z isomerization. Conversely, the hydroxylated analogue (Sw–OH–C12) mixes nearly ideally with DPPC but occupies different depths within the bilayer depending on isomerization state (E near the interface, Z internalized), resulting in an increase in surface pressure and a decrease in vesicle size upon E→Z isomerization. The two-photon– responsive photoswitches reported herein appears thus as versatile tools for the optical control of membrane architecture in biological environments where NIR light is required.