Background: We have previously developed a gold nanoparticle (GNP)-based anti-cancer immunotherapy, termed integrated glyco-nanovaccine (iGN). The iGN is composed of GNPs conjugated to a synthetic toll-like receptor (TLR) 7 ligand, an antigen peptide, and a mannose sugar chain. However, the effect of the combination of different sugar chains and antigen peptides on iGN-mediated anticancer immunotherapy remains to be elucidated.
Objective: We compared the anti-tumor effects of two different sugar chains: α-mannose and sialic acid.
Results: We showed that not only the sugar chain but also the antigen peptide plays a pivotal role in iGN uptake by immune cells. In contrast to α-mannose, which promoted GNP internalization by bone marrow-derived dendritic cells (BMDC), sialic acid modification resulted in limited cellular uptake. The integration of major histocompatibility complex class I-restricted ovalbumin peptides drastically changed this cellular recognition pattern, particularly for sialic acid-modified iGN. The peptide largely improved the uptake of nanoparticles, delivery of the TLR 7 ligand, and subsequent activation of the type I interferon pathway in BMDC. Sialic acid-modified iGN demonstrated comparable induction of CD8+ T cell and efficacy of anti-cancer therapy to α-mannose-modified iGN in an EG7 syngeneic mouse tumor model.
Conclusions: These results indicate that antigens, and not only the sugar chain, critically determine both the cellular internalization and immunotherapeutic efficacy of iGNs. This study presents a new design principle for glyco-nanovaccines, where peptides override glycan synergy and determine therapeutic efficacy.
Keywords: TLR7 ligand; antigen peptide; gold nanoparticle; immunotherapy; sugar chain.
© 2025 The Author(s). Cancer Medicine published by John Wiley & Sons Ltd.