Reprogramming the genome of M13 bacteriophage for all-in-one personalized cancer vaccine

Peptide-based vaccines face limitations in immunogenicity and stability, and challenges in co-delivering antigens and adjuvants effectively. Virus-based nanoparticles, particularly M13 bacteriophage, present a promising solution due to their genetic modifiability, intrinsic adjuvanticity, and efficient antigen presentation capabilities. Here we developed a programmable M13 phage-based personalized cancer vaccine enabling single-step antigen-adjuvant assembly. Specifically, we designed a reprogrammed (RP) phage platform that precisely regulates Toll-like receptor 9 activation by programming its genome sequence and modulates antigen density through genetic engineering. Vaccination studies with RP phages demonstrated that the immune response could be modulated by fine-tuning the adjuvanticity and antigen density, revealing an optimal antigen dose and adjuvanticity for maximum vaccine efficacy. The RP phage induced a remarkable 24-fold increase in neoantigen-specific CD8 ⁺ T cells and eradicated established MC-38 tumors when combined with anti-PD-1 therapy. These findings highlight the RP phage's potential as a powerful nanovaccine platform for personalized cancer vaccines.