Lipopeptide Hydrogel Possesses Adjuvant‐Like Properties for the Delivery of the GPC‐3 Peptide‐derived Antigen

Abstract Peptide‐based cancer vaccines are attractive as they can elicit antigen‐specific cytotoxic T lymphocytes (CTLs) with minimal side effects. However, low immunogenic responses have delayed their translation to the clinic. Adjuvants, which are required in vaccines to boost immunogenicity, currently lack the ability to simultaneously induce specific cell‐mediated effects and act as a delivery system. These concerns are addressed by engineering a novel class of adjuvants; lipopeptide hydrogels (LPHs). Myristic acid conjugated to diphenylalanine (Myr‐FF), myristic acid diphenylalanine‐tyrosine (Myr‐FFY), and combination gel (Cogel) are synthesized and tested for immune modulation. They are loaded with a glypican‐3 (GPC‐3)‐derived peptide designed for targeting hepatocellular carcinoma (HCC). The LPHs enable the sustained release of the GPC‐3 peptide over two weeks, followed by antigen uptake by antigen‐presenting cells (APCs). These LPHs are shown to act as a toll‐like receptor (TLR)‐2 agonist, cause an upregulation of costimulatory molecules (CD80, CD83, CD86), and the secretion of cytokines (IL‐6, TNF‐α, etc). In vivo studies showed that LPHs cause an increase in leukocyte infiltration within LNs with no visible toxicity. These LPHs exhibit adjuvant‐like characteristics, thus providing a promising platform for future investigation in enhancing peptide‐based vaccine efficacy.