Cancer vaccines utilizing nanoparticle (NP) structures that integrate antigens and adjuvants to enhance delivery and stimulate immune responses are emerging as a promising avenue in cancer immunotherapy. However, the development of cancer vaccines has been significantly hindered by the low immunogenicity of tumor antigens. To address this challenge, substantial efforts have been made in developing innovative adjuvants to elicit effective immune responses. In this study, we develop a NP cancer vaccine assisted by a polysaccharide derivative adjuvant, designed through a computational strategy, to evoke effective antigen-specific antitumor immunity. Using TLR4 as the putative receptor, we conducted a comprehensive evaluation of a prescreening library consisting of 34 inulin derivatives through docking and molecular dynamics simulation. Consequently, a new derivative, benzoylated inulin (InBz), is selected as the most promising TLR4 agonist. The adjuvant effect of InBz is evaluated by fabricating InBz NPs encapsulating the model antigen ovalbumin (OVA). In vitro, InBz-OVA NPs effectively activate the TLR4 signaling pathways and facilitate dendritic cell maturation, thereby enhancing the antigen delivery and presentation. In vivo, InBz-OVA NPs outperform a commercial aluminum-based adjuvant, elicit robust antibody titers, induce antigen-specific cytotoxic T lymphocytes, and achieve significant tumor suppression in murine models. Besides, the adjuvant effects of other representative derivatives, namely, acetylated and chloroacetylated inulin, with moderate and low potential from the library, are also chemically synthesized and experimentally evaluated and found to be in agreement with computational predictions, confirming the credibility of the strategy. This study provides an effective platform for the pursuit of efficient polysaccharide-based vaccine adjuvants.
Keywords: cancer immunotherapy; inulin; molecular simulation; polysaccharide; vaccine adjuvant.