Abstract

The development of targeted drug delivery systems is crucial for enhancing therapeutic efficacy and reducing systemic toxicity. Liposomal formulations of the antibiotic levofloxacin, particularly when surface-modified with mucoadhesive polymers like mannosylated chitosan (ChiMan), represent a promising strategy for localized delivery, such as in pulmonary or ocular applications. This study investigates the critical role of the **Drug-to-Lipid-Ratio (D/L)** in governing the physicochemical properties and fine structure of levofloxacin-loaded liposomes. Using a combination of advanced biophysical techniques, including cryo-transmission electron microscopy (cryo-TEM) and small-angle X-ray scattering (SAXS), we systematically characterized how varying the D/L ratio influences the internal organization of the drug precipitate and the integrity of the lipid bilayer. Our findings reveal that the D/L ratio is a primary determinant of liposome morphology, dictating the formation of distinct internal nanostructures that directly impact drug loading capacity and release kinetics. Furthermore, we elucidated the molecular details of the complex formation between the optimized liposomal structures and mannosylated chitosan, highlighting the specific electrostatic and hydrogen bonding interactions that drive the surface coating. These results provide fundamental insights into the rational design and optimization of lipid-polymer hybrid nanoparticles for advanced drug delivery, with significant implications for improving the therapeutic index of encapsulated antimicrobial agents.