Yeast β-Glucan-Grafted Glycogen Nanoparticles for Macrophage-Targeted Precise Delivery of CpG Oligodeoxynucleotides: Implications for Immunotherapy Applications

Immunostimulatory CpG ODNs activate an immune response through recognition with TLR9. CpG ODNs demonstrate great potential in immunotherapy. However, their application is limited by drawbacks such as rapid nuclease degradation, low cellular uptake, and deficient release in TLR9-localized endo/lysosome. Precise transportation of CpG ODNs into endo/lysosomes of immune cells is crucial for promoting the immunostimulatory effect. In this work, a macrophage-targeted CpG ODNs delivery system was fabricated. Yeast β-glucan grafted glycogen (Gly–Glu) was synthesized and used as the carrier. Gly–Glu was positively charged, which encapsulated CpG ODNs and protected them against DNase digestion. Gly–Glu possessed a high CpG ODNs loading efficiency. Gly–Glu/CpG specifically recognized macrophages through dectin-1 and thus showed higher cellular uptake via dectin-1-mediated endocytosis. Furthermore, Gly–Glu/CpG could be broken down by a degradation enzyme such as α-glucosidase in endo/lysosome, which significantly accelerated CpG ODNs release and further facilitated their interaction with TLR9. Consequently, Gly–Glu/CpG induced a higher immunostimulation. Our work offers a promising approach for precisely delivering CpG ODNs to macrophages, which brings hope for immunotherapy.