An Antigen‐Capturing Nanoparticle Harnesses the Protein Corona to Enhance Antigenic Immunogenicity and Clonal Diversity against Cancer

ABSTRACT Neoantigen vaccines are often limited by inter/intra‐patient heterogenicity as well as labor‐intensive production. Balancing personalization and universality remains challenging. While the protein corona that forms on nanoparticles has long been viewed as a detrimental factor, it can be strategically harnessed to align with an individual's unique antigenic landscape. Here, we introduce a “BET‐dependent Antigen‐capturing ImmunoTransmitter (BAIT)” as an in situ nanovaccine to expand the antigenic breadth and clonal diversity of antitumor immunity. By synthesizing a series of metal–organic frameworks with tunable defect concentrations and pore densities, we find that the antigen‐capturing capacity is positively correlated with the BET surface area. BAIT keeps “Off” in vivo but turns “On” in the acidic tumor microenvironment, where it spontaneously creates an active antigen corona for uptake and cross‐presentation by type‐I conventional dendritic cells (cDC1s), increasing both availability and immunogenicity of endogenous antigens. Consequently, BAIT elicits broad‐spectrum T cell responses against tumor heterogenicity. Depletion of cDC1s in Batf3 ^−/− mice abolishes its effect. BAIT further synergizes with treatments that increase local tumor antigen load, such as chemotherapy and radiotherapy, to eradicate cold tumors and prevent recurrence. Its feasibility is validated in human patient samples.