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Being a Th2 stimulator, classic aluminum salt-based adjuvants only stimulate weak cellular immune responses that are required for vaccination against intracellular viruses or cancerous cells. As a third-generation bisphosphonate, zoledronate (ZOL) can enhance antigen cross-presentation by inhibiting key enzymes of the mevalonate pathway. Here, we developed the subunit antigen ovalbumin (OVA) and ZOL co-loaded aluminum hydroxide nanoparticles (APN-OVA-ZOL) and investigated their capacity for inducing cellular immune responses against the antigen. Our results showed that the developed nanovaccines could successfully encapsulate OVA and ZOL, and enabled efficient lymph node delivery. Benefited by the mevalonate pathway inhibition effect of ZOL, APN-OVA-ZOL significantly promoted cross-presentation. As a result, APN-OVA-ZOL induced robust cellular immunity, including the activation of T and B cells. In a EG7-OVA tumor-bearing murine model, APN-OVA-ZOL significantly inhibited the tumor growth and prolonged mice survival. This work provided a strong empirical foundation indicating that zoledronate-loaded aluminum salt nanovaccines had a strong potency for cancer immunotherapy.
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