lipid-based nanoparticles (LNPs), particularly liposomes, have gained prominence throughout the pharmaceutical sector as a hopeful means for transporting a range of therapeutic agents. Improving LNPs stability is crucial in pharmaceuticals, and drug delivery systems to ensure their effectiveness and reliability. The current research was undertaken to design a pH-responsive hyaluronic acid-modified gold nanoparticle-stabilized cationic liposome (SPC/DOPE/DOTAP) system (HA-SH/AuNPs@liposomes) to improve the stability of liposomes. This was achieved through a post-microfluidics conjugation technique to encapsulate the 5-fluorouracil (5-FU) anticancer drug, usually employed in nonmelanoma skin cancer (NMSC) treatment. Microfluidics is an emerging technology that can be employed as a powerful tool for designing nanoscale liposomes with highly uniform size distributions and acceptable colloidal stability. Utilizing a microfluidics toroidal mixer, affixed HA-SH/AuNPs (size: 12.56 ± 1.65 nm) to positively charged liposomes (size: 75 ± 0.68 nm and PDI: 0.032 ± 0.0021). These liposomes exhibited strong stability, limited fusion propensity, and minimal cargo release at neutral pH. The gold stabilizers detached in an acidic environment, releasing encapsulated therapeutic agents. The dynamic light scattering (DLS) analysis results indicate that HA-SH/AuNPs@Liposomes (size: 102.2 ± 1.3 nm and PDI: 0.11 ± 0.01) exhibit greater stability than bare liposomes over 4 weeks at 4 °C. This enhanced stability can be attributed to the presence of HA-SH/AuNPs in the liposomal structure. This research outlines a systematic method to optimize the size rapidly and PDI of liposomes by employing the Design of Experiments (DoE). The results highlighted that utilizing both the microfluidic technique and gold nanoparticle-stabilized liposomes offers benefits for creating controlled drug release formulations. This approach leads to enhanced biopharmaceutical characteristics and improved scalability of liposomal formulations.
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