One-Step Microfluidic Manufactured Fucose-Decorated Sweetosomes Choose the Time and the Road for Their Intracellular...

Carbohydrate‑functionalized liposomes are promising drug‑delivery systems due to their biocompatibility, biodegradability, low toxicity, and ability to mediate targeted cell interactions. However, conventional functionalization strategies rely on multi‑step chemical conjugations that introduce variability, hinder large‑scale production, and compromise formulation stability. Here, we overcome these limitations by achieving liposome functionalization without surface chemistry. We introduce "sweetosomes," a newly formulated class of sugar‑decorated liposomes designed for cancer targeting, which promote more specific and active cellular uptake, prolonged intracellular retention, and enhanced endosomal escape. We show that organelle acidity can be selectively modulated by fucosylated sweetosomes, supporting their role in facilitating endosomal escape an essential step for the cytoplasmic delivery of biological therapeutics. Fucosylated sweetosomes and blank liposomes enter cells but traffic through distinct endosomal pathways; indeed, fucose residues appear to alter endosomal maturation and function. Our findings validate fucosylated sweetosomes as optimized lipid nanostructures for intestinal cancer targeting, demonstrating significantly improved curcumin delivery, primarily via the caveolae pathway. Finally, fucosylated sweetosomes highlight translational potential, due to their prolonged plasma persistence, as detected by ex vivo plasma and blood‑cell analyses.