Dendritic Lipopeptide Nanovaccines Orchestrate Multi‐Pattern Recognition Receptors Activation and Potentiate Antitumor Immunity

Precise control over the spatial and temporal delivery of antigens and adjuvants is essential for eliciting effective and durable immune responses. Here, we report a self-assembling nanovaccine platform based on dendritic lipopeptides (DLPs) that integrate delivery and immune-stimulation through a structurally defined design. DLPs are constructed by conjugating structurally optimized lipid tails to second-generation lysine- or arginine-rich dendritic scaffolds. Systematic engineering of the lipid domain allows for precise fine-tuning of the amphiphilic structure, yielding molecular candidates with significantly enhanced TLR2/4 agonist activity. These structures facilitate antigen uptake and cross-presentation by APCs in a spatiotemporally regulated manner. Co-assembly with lipidated peptide antigens and a lipid-modified TLR7/8 agonist yields nanoscale vaccines capable of orchestrating synergistic multi-pattern recognition receptor (PRR) activation. In murine melanoma and colorectal tumor models, these nanovaccines elicit robust cytotoxic T lymphocyte responses, enhance antigen-specific killing by up to 40%, and induce significant tumor regression. This work presents a chemically defined, modular nanoplatform that mimics key features of pathogen-like immunity and provides a rational strategy for engineering minimalist cancer vaccines with high efficacy and translational potential.