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

Abstract

Nanovaccines co-assemble antigens and adjuvants to elicit robust immuneresponses but often require complex synthesis and post-modificationprocedures. Here, a programmable nanovaccine platform based on the M13bacteriophage is developed for the scalable production of vaccines andsingle-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 preciselycontrolled. With a novel molecular engineering approach, the antigen densityis tuned from 13.6% to 70.3%. A systematic modulation reveals an optimaladjuvanticity at a constant antigen density for maximum anti-tumor CD8+ Tcell response, and vice versa, using the model antigen SIINFEKL. The M13phage-based nanovaccine induces durable memory immunity lasting over ayear. In addition, a 24-fold increase in neoantigen-specific CD8+ T cellfrequency is achieved when increasing both the adjuvanticity and antigendensity. Furthermore, when combined with anti-PD-1 therapy, the M13phage-based personalized vaccine eradicates established MC-38 tumors in75% of treated animals and they develop 100% resistance against tumorinvasion when challenged 5 months after treatment. These findings establishM13 phage as a powerful and versatile nanovaccine platform withtransformative potential for personalized cancer immunotherapy.