High-Density Inverted Micellar Intermediates Promote Membrane Fusion of Cationic Liposomes in Drug Delivery

Area of Science:

• Biotechnology
• Materials Science
• Cell Biology

Background:

• Liposomes are crucial carriers for pharmaceuticals, but inefficient endosomal uptake limits their therapeutic potential.
• Fusogenic liposomes offer a solution by directly delivering cargo into the cytoplasm, bypassing endosomal degradation.

Purpose of the Study:

• To investigate the phase properties of highly fusogenic liposomes.
• To identify structural features responsible for efficient membrane fusion at physiological temperatures.

Main Methods:

• Preparation of giant and small cationic liposomes with high fusion efficiency.
• Analysis of thermal phase behavior using fluorescence microscopy, solid-state NMR, small-angle neutron scattering (SANS), and cryo-electron microscopy.

Main Results:

• Liposomes exhibited temperature-dependent phase behavior, with a lamellar phase at ≤25 °C and low fusion capacity.
• At physiological temperatures (≥37 °C), inverted micellar intermediates and interlamellar attachments were observed within the lamellar phase.
• Cryo-electron tomography resolved the structures of these metastable fusion intermediates.

Conclusions:

• Metastable fusion intermediates, observed at physiological temperatures, are critical for the high membrane fusion efficiency of these liposomes.
• Optimizing liposomal composition based on these phase properties can enhance their utility in biomedical applications for efficient drug delivery.