Fabrication of stable chitosan-liposomes via flash nanoprecipitation for efficient fluconazole encapsulation

Liposomes, as effective drug delivery systems, face limitations in their low efficiency of traditional preparation methods and inherent physical instability. In this study, we systematically compared two strategies based on Flash Nanoprecipitation (FNP) technology for the rapid and controllable preparation of chitosan hybrid liposomes. We hypothesize that the "one-step" FNP method, which mixed chitosan and lipid solutions simultaneously, potentially enabled direct co-assembly between chitosan and lipid molecules, so that chitosan molecules likely embedded within the phospholipid bilayer, resulting in liposomes with more uniform structure and smaller particle size (∼70 nm). Meanwhile, the "two-step" FNP method, which mixed chitosan with preformed liposomes, likely yielded a core-shell structure through chitosan adsorption onto the liposome surface. The one-step FNP prepared particles exhibit excellent long-term storage stability and resistance to pH and ionic strength variations, likely due to the steric effect provided by the embedded polymer chains. To investigate the drug loading capability of FNP prepared chitosan-liposomes, we encapsulated an antifungal drug, fluconazole, into these hybrid nanoparticles. Compared to the free drug, the drug-loaded liposomes not only achieved sustained release, but also reduced the minimum inhibitory concentration against Candida albicans by an order of magnitude. This study demonstrates that FNP technology, particularly the one-step strategy, provides a robust platform for constructing polymer hybrid liposomes, showing potential for enhancing the delivery and functionality of poorly soluble drugs.