Peptide Modulation Overrides Glycan Synergy in Gold Nanoparticle-Based Vaccines for Cancer Immunotherapy

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.

We compared the anti-tumor effects of two different sugar chains: α-mannose and sialic acid.

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.

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.