A Programmable Nanovaccine Platform Based on M13 Bacteriophage for Personalized Cancer Vaccine and Therapy

Abstract Nanovaccines co‐assemble antigens and adjuvants to elicit robust immune responses but often require complex synthesis and post‐modification procedures. Here, a programmable nanovaccine platform based on the M13 bacteriophage is developed for the scalable production of vaccines and single‐step modular engineering of adjuvanticity, length, and antigen density. By reprogramming the sequence and size of the noncoding phage genome, the Toll‐like receptor 9 activation and the length of the phage are precisely controlled. With a novel molecular engineering approach, the antigen density is tuned from 13.6% to 70.3%. A systematic modulation reveals an optimal adjuvanticity at a constant antigen density for maximum anti‐tumor CD8 + T cell response, and vice versa, using the model antigen SIINFEKL. The M13 phage‐based nanovaccine induces durable memory immunity lasting over a year. In addition, a 24‐fold increase in neoantigen‐specific CD8 + T cell frequency is achieved when increasing both the adjuvanticity and antigen density. Furthermore, when combined with anti‐PD‐1 therapy, the M13 phage‐based personalized vaccine eradicates established MC‐38 tumors in 75% of treated animals and they develop 100% resistance against tumor invasion when challenged 5 months after treatment. These findings establish M13 phage as a powerful and versatile nanovaccine platform with transformative potential for personalized cancer immunotherapy.