Dendritic Lipopeptide Nanovaccines Orchestrate Multi-Pattern Recognition Receptors Activation and Potentiate...

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.