In cancer patients, visual identification of sentinel lymph nodes (LNs) is achieved by the injection of dyes that bind avidly to endogenous albumin, targeting these compounds to LNs where they are efficiently filtered by resident phagocytes,. Here we translate this “albumin hitchhiking” approach to molecular vaccines, via the synthesis of amphiphiles (amph-vaccines) comprised of an antigen or adjuvant cargo linked to a lipophilic albumin-binding tail by a solubility-promoting polar polymer chain. Structurally-optimized CpG-DNA/peptide amph-vaccines exhibited dramatic increases in LN accumulation and decreased systemic dissemination relative to their parent compounds, leading to 30-fold increases in T-cell priming and enhanced anti-tumor efficacy while greatly reducing systemic toxicity. Amph-vaccines provide a simple, broadly-applicable strategy to simultaneously increase the potency and safety of subunit vaccines.
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