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Bifunctional Phage Particles Augment CD40 Activation and Enhance Lymph Node-Targeted Delivery of Personalized Neoantigen Vaccines

Xiaotong Chen,Lei Lei,Jiayao Yan,Xingzhou Wang,Lin Li,Qin Liu,Ying Wang,Tianran Chen,Jie Shao,Lixia Yu,Zijian Li,Lijing Zhu,Lifeng Wang,Baorui Liu

Although personalized neoantigen cancer vaccines have emerged as a promising strategy for cancer treatment, challenges remain to develop immune-stimulatory carriers which allow simultaneous transport of adjuvants and vaccines to lymph nodes (LNs). With inherent immunogenicity, genetic plasticity, and efficiency for large-scale production, M13 phages represent an attractive platform for vaccine delivery as natural bionanomaterials. Here, we report the discovery of an anti-CD40 designed ankyrin repeat protein (DARPin) and propose a bifunctional M13 ph age for neoantigen delivery based on this anti-CD40 DARPin protein (M13CD40). M13CD40-based neoantigen vaccines show improved accumulation and prolonged antigen retention in LNs compared with nontargeting phage vaccines due to the abundance of CD40-positive cells in LNs. Besides the intrinsic immunogenicity of phages, M13CD40-based neoantigen vaccines also benefit from additional CD40 stimulation due to multiple copies of anti-CD40 DARPins displayed on M13CD40 phages. Subcutaneous immunization with M13CD40-based neoantigen vaccines results in more robust antigen-specific immune responses and superior antitumor efficacy in poorly immunogenic tumor models compared with nontargeting phage vaccines. Combination therapy with PD-1 blockade further enhances T cell cytotoxicity and improves tumor control. To summarize, our findings highlight M13CD40 as a CD40 nanoagonist as well as an efficient vehicle for LN-targeted delivery of personalized neoantigen vaccines.