Spatially Programmed Ferritin Nanocage Vaccine Enables DC‐Biased Delivery and Enhanced Antigen Cross‐Presentation

ABSTRACT

Cancer vaccines can induce durable antitumor immunity, yet their therapeutic efficacy remains limited by inefficient lymphatic trafficking, insufficient dendritic cell (DC) engagement, and suboptimal antigen presentation. Here, we developed Fe@DCpep‐Fn‐OVA, a spatially engineered ferritin nanocage vaccine integrating multivalent antigen display, DC‐biased delivery, and an intrananocage functional module within a single protein scaffold. The ferritin shell was genetically programmed to display the OVA _257–264 epitope (SIINFEKL) and a DC‐engaging peptide (DCpep), whereas an iron‐mineralized catalytic component was confined within the internal cavity. This orthogonal shell–cavity architecture enables coordinated extracellular immune cell recognition and intracellular immune regulation. Following subcutaneous administration, Fe@DCpep‐Fn‐OVA exhibited enhanced accumulation in draining lymph nodes (dLNs) and increased association with CD11c ⁺ DCs. The cavity‐confined iron component retained acid‐responsive peroxidase‐like activity and provided localized intracellular regulatory cues, promoting DC maturation, H‐2K ^b /SIINFEKL presentation, and antigen‐specific CD8 ⁺ T cell activation. In therapeutic subcutaneous and intravenous B16‐F10‐OVA lung‐colonization models, Fe@DCpep‐Fn‐OVA effectively inhibited tumor growth and lung colonization, outperforming OVA plus Poly(I:C). Moreover, prophylactic immunization induced durable CD8 ⁺ memory T cell responses and protected mice against lung colonization upon tumor challenge. These findings establish ferritin shell–cavity compartmentalization as a programmable strategy for next‐generation cancer vaccination.