Enhanced Antibacterial Properties of Lyotropic Liquid Crystalline Nanoparticles via Curvature Modulation

Lyotropic liquid crystalline nanoparticles (LCNPs) have shown significant potential as nanocarriers for antibiotic delivery and as an alternative polytherapy strategy with antibiotics. Mechanistic studies indicate that these nanoparticles can fuse with bacterial membranes, causing destabilization and lipid extraction. While current research on LCNPs has primarily focused on surface functionality to enhance antibiotic delivery based on their known membrane fusion properties, the role of LCNP curvature in enhancing fusion and penetration remains unexplored. Specifically, understanding how structural design, such as the optimization of lamellar and bicontinuous cubic phases, affects membrane fusion capabilities could unlock new opportunities for more effective therapeutic-loaded LCNPs and polytherapy approaches. Herein, we have synthesized lamellar vesicles with zero curvature and then structurally modulated into non-lamellar primitive (P-cubosomes) and diamond (D-cubosomes) cubic phases with increasingly negative curvatures. The tested polytherapy of three distinct LCNPs with daptomycin against methicillin-resistant Staphylococcus aureus (MRSA) strains, demonstrating that manipulating LCNP curvature enhances their synergy with daptomycin. Fluorescent and electron microscopy analyses demonstrated that increased negative curvature enhances membrane interactions, establishing a clear link between LCNP’s nanostructures and antimicrobial effectiveness, following the order of vesicles < P-cubosomes < D-cubosomes, with D-cubosomes showing the strongest effects. Neutron reflectometry using model membranes provided Ångström-level details, confirming that curvature positively impacts membrane interaction. This study presents the first experimental evidence linking LCNP curvature to enhanced interaction with bacterial membranes and marks the first application of LCNPs against MRSA, suggesting that curvature manipulation could serve as a novel strategy for designing more potent antimicrobial agents.