A Sodium Alginate‐Based Multifunctional Nanoplatform for Synergistic Chemo‐Immunotherapy of Hepatocellular Carcinoma

Abstract Efficient hepatocellular carcinoma (HCC) treatment remains a significant challenge due to the inherent limitations of traditional strategies. The exploration of polysaccharides’ natural immunity for HCC immunotherapy is rarely explored. For this purpose, facile construction of a multifunctional nanoplatform, biotinylated aldehyde alginate‐doxorubicin nano micelle (BEACNDOXM) is reported in this study for synergistic chemo‐immunotherapy by using constant β‐D‐mannuronic acid (M) units and modulated α‐L‐guluronic acid (G) units in the alginate (ALG) structure. The M units show natural immunity and specific binding ability with mannose receptors (MRs) via strong receptor‐ligand interactions, and the G units serve as highly reactive conjugation sites for biotin (Bio) and DOX. Therefore, this formulation not only integrates the natural immunity of ALG and the immunogenic cell death (ICD) triggering function of DOX, but also shows dual targeting properties to HCC cells via MRs and Bio receptors (BRs)‐mediated endocytosis. Notably, BEACNDOXM mediates a tumor inhibitory efficiency 12.10% and 4.70% higher than free DOX and single targeting aldehyde alginate‐doxorubicin nano micelle controls, respectively, at an equivalent DOX dose of 3 mg kg⁻¹ in Hepa1‐6 tumor‐bearing mice. This study reports the first example of integrating the natural immunity of ALG and the ICD effect of anticancer drugs for enhanced chemo‐immunotherapy of HCC.