A Green, Solvent- and Cation-Free Approach for Preparing 5-Fluorouracil-Loaded Alginate Nanoparticles Using Microfluidic Technology.

: Alginate nanoparticles (NPs) are commonly synthesised using either an emulsion technique that involves organic solvent use or ionotropic gelation utilising multivalent cations, e.g., Ca. However, the extensive use of organic solvents imposes detrimental effects on the ecosystem, and using multivalent cations as crosslinkers could eventually lead to the leakage of these cations, thus disrupting nanoparticle matrices. Therefore, this study aimed to overcome the limitations of these techniques by eliminating the usage of organic solvents and multivalent cations. : In this research, alginate nanoparticles were synthesised using proton gelation by microfluidic technology through protonating alginate carboxylate groups to crosslink alginate chains through H-bond formation. : The prepared acid-gelled alginate nanoparticles demonstrated an MHD circa 200 nm and a PDI of less than 0.4 at pH 0.75. Moreover, 5-FU was successfully encapsulated into acid-gelled alginate nanoparticles and displayed a high EE% of around 30%, comparable to the EE% at high alginate concentration and molecular weight (0.4 H-ALG) achieved by Ca-crosslinked alginate nanoparticles; however, 5-FU NPs had superior characteristics, i.e., a lower MHD (around 500 nm) and PDI (<0.5). The optimum formula (0.4 H-ALG) was explored at various pH values, i.e., low pH of 4.5 and high pH of 10, and alginate NPs produced by acid gelation demonstrated high stability in terms of MHD and PDI, with slight changes at different pH values, indicating stable crosslinking of alginate matrices prepared by technology compared with Ca-crosslinked alginate NPs. : In conclusion, this research has invented an ecologically friendly approach to producing acid-gelled alginate nanoparticles with superior characteristics compared with the conventional methods, and they could be harnessed as nanocarriers for therapeutics delivery (5-FU). Also, this research offers a promising approach for developing eco-friendly and biocompatible drug carriers. The produced nanoparticles have the potential to enhance drug stability, improve controlled release, and minimise toxic effects, making them suitable for pharmaceutical applications.