A fluorinated poly(amino acid) nanovaccine with spatiotemporally encoded innate priming and antigen cross-presentation for tumor immunotherapy

The efficacy of cancer vaccines depends on spatiotemporally coordinated innate immune priming and antigen cross-presentation, but this hierarchy remains difficult to control with existing delivery platforms. Here, we report a fluorinated diethylenetriamine-modified poly(aspartic acid) nanovaccine platform, termed DET-F, and identify DET-F30 as the optimized formulation for antigen delivery and immune activation. Perfluorooctyl side chains promote early endosomal toll-like receptor 3 (TLR3) associated innate immune signaling and dendritic cell maturation, whereas the pH-responsive polymer backbone facilitates subsequent endosomal escape and cytosolic antigen release. This chemically encoded sequence enables delayed yet enhanced antigen cross-presentation in mature dendritic cells. DET-F30/antigen nanoparticles display efficient antigen loading and cellular uptake, activate TLR3-related innate immune pathways, and elicit robust antigen-specific CD8 + T cell immunity. In multiple tumor models, DET-F30-based vaccination suppresses tumor growth and metastasis, prolongs survival, and enhances post-surgical anti-PD-1 therapy. This work establishes fluorinated poly(amino acid)s as minimalist self-adjuvant nanovaccine vectors and demonstrates that precise polymer-architecture encoding can orchestrate sequential innate immune activation and antigen processing for improved cancer immunotherapy.