Aluminum nanoparticles deliver a dual-epitope peptide for enhanced anti-tumor immunotherapy

Tumor peptide vaccines contain only key amino acid sequences of tumor neoantigens, and therefore can provide precise activation of immune responses. Recent research has found that short peptide vaccines restricted to MHC-I epitopes are insufficient to activate effective CD8⁺ T cell responses for tumor elimination, and assistance from CD4⁺ T cell immunity could significantly improve the therapeutic outcome. Herein, we proposed an innovative peptide vaccine strategy to simultaneously activate CD8⁺ and CD4⁺ T cell responses by combining MHC-I and MHC-II epitopes into one long peptide antigen. To further strengthen the anti-tumor immune response induced by this dual-epitope peptide, we engineered a PEG derivative (PpASE) stabilized aluminum nanoparticle for delivering the synthetic long peptides (ANLs). The synthesized nanovaccine with a diameter of ~100 nm showed good stability and enhanced antigen uptake by antigen-presenting cells (APCs). As a result, ANLs promoted the presentation of MHC-I epitope in APCs and induced stronger activation and proliferation of CD8⁺ T cells as compared to aluminum nanoparticle loaded with MHC-I epitope restricted peptides (ANSs). After subcutaneous vaccination, the developed nanovaccine significantly inhibited tumor growth and prolonged mouse survival in both B16-OVA and B16F10 tumor models. Finally, ANLs were also able to elevate the maturation level of human dendritic cells (DCs), showing a great possibility of clinical translation.