An NIR-II-Traceable Nanovaccine Programs Systemic Antigen Residence to Establish Checkpoint-Responsive Progenitor-Exhausted CD8-Positive T-Cell Reservoirs for Effective Cancer Immunotherapy.

Nanovaccines offer an opportunity to define where, how long, and in which immune niches antigens are presented. However, many cancer vaccine systems still preferentially induce transient effector CD8+ T-cell responses with limited capacity to sustain checkpoint-responsive immunity. Here, we report NIRVax, a second near-infrared window (NIR-II)-traceable, long-residence nanovaccine that couples real-time in vivo tracking to programmable systemic antigen residence. NIRVax is assembled from a triphenylamine-based NIR-II fluorophore and distearoyl phosphoethanolamine-polyethylene glycol 2000 (DSPE-PEG2000), followed by covalent conjugation of the model protein antigen ovalbumin (OVA). After intravenous administration, NIRVax sustains antigen residence across secondary lymphoid organs (SLOs), with lymphoid signals peaking at day 4 postinjection followed by gradual clearance. This material residence profile enhances antigen uptake, dendritic cell maturation, and stem-like CD8+ T-cell generation. NIRVax also accumulates at bone-associated sites, where it is associated with hematopoietic remodeling, myeloid-biased differentiation, and a reduced suppressive myeloid output. Functionally, systemic NIRVax vaccination establishes antigen-specific progenitor-exhausted CD8+ T-cell (TPEX) reservoirs across lymphoid tissues and the tumor microenvironment (TME). Upon programmed death-ligand 1 (PD-L1) blockade, these reservoirs are mobilized into effector CD8+ T-cell responses, leading to tumor immune remodeling, epitope spreading, and improved melanoma control. These findings establish spatiotemporal antigen residence as an engineerable biomaterial parameter for shaping the CD8+ T-cell fate and provide a NIR-II-traceable nanovaccine strategy for potentiating checkpoint cancer immunotherapy.