Enhanced Antibacterial Properties of Lyotropic Liquid Crystalline Nanoparticles via Curvature Modulation

ABSTRACT Lyotropic liquid crystalline nanoparticles (LCNPs), including cubosomes, are increasingly investigated as antimicrobial nanomaterials because non‐lamellar lipid nanoparticles can fuse with biological membranes, exchange lipids, and improve antimicrobial delivery or antibiotic combination treatment. However, prior studies have mainly addressed fusion, uptake, encapsulation, or payload stabilization, rather than testing whether retained internal curvature can be isolated as a design variable for antibacterial potentiation in a matched LCNP series. Herein, we generated lamellar vesicles, primitive cubosomes (P‐cubosomes, Im3m ), and diamond cubosomes (D‐cubosomes, Pn3m ) from the same phytantriol/DPPS lipid system. When combined with free daptomycin, rather than being used as drug‐loaded carriers, these LCNPs exhibited curvature‐dependent potentiation hierarchy against methicillin‐resistant Staphylococcus aureus (MRSA), vesicles < P‐cubosomes < D‐cubosomes. Fluorescence imaging, electron microscopy, and neutron reflectometry showed progressively stronger membrane association, lipid extraction, and bilayer disruption with increasingly negative curvature. In a murine bacteremia model using a sub‐optimal daptomycin regimen, the same curvature‐dependent efficacy trend was retained in vivo, providing proof‐of‐concept support rather than therapeutic validation. This study provides direct experimental evidence, in a matched antibacterial LCNP system, that retained internal curvature modulates membrane remodeling and potentiates daptomycin against MRSA.