Glycosylated Human Heavy Chain Ferritin Nanoparticles Enhance Liver-Targeted Drug Delivery

As a ubiquitous iron-storage protein, human heavy chain ferritin (FTH) is widely used in drug delivery. Recent advances in FTH engineering highlight the therapeutic and translational potential of glycosylation. We herein report the biosynthesis of various glycosylated FTHs (Glc-FTH, Glc_n-FTH, and Gal-Glc-FTH) in Escherichia coli via enzymatic methods. Their self-assembly and thermal stability are unaffected by glycosylation, while the acid sensitivity is significantly enhanced, enabling depolymerization in a milder and more controllable manner. Gal-Glc-FTH exhibits exceptional advantages (low cytotoxicity, low immunogenicity, minimal apoptosis-inducing ability, prolonged half-life, and strong hepatic targeting), which collectively enhance its applications in hepatic targeted drug delivery. Although Glc_n-FTH also significantly enhances hepatic targeting, its induction of high-titer antibodies indicates that it is more suitable for development as a vaccine carrier. Our findings emphasize the critical role of glycans in FTH properties, providing novel strategies and insights for cancer-targeted drug delivery systems.