Layer‐by‐Layer Deposition of Antigen Peptides on Bifidobacterium for Subintestinal Lymphatic System‐Guided Personalized Tumor Immunotherapy

Abstract Gut‐associated lymphoid tissue (GALT) possesses a highly specialized immune system and is rational as a foothold for oral tumor vaccines. Here, a noninvasive oral vaccine (Bif‐OVA‐Ocur) is designed to engage GALT, inducing both intestinal mucosal and systemic immunity for tumor therapeutics. The vaccine uses Bifidobacterium (Bif) as a delivery vehicle for tumor antigen peptides, which are coated with antigen peptides (OVA) and oxidized curdlan (Ocur) in a layer‐by‐layer (LBL) manner. Upon oral administration, Bif‐OVA‐Ocur is efficiently directed to Peyer's patches (PPs) in the intestines and further presented to antigen‐presenting cells (APCs), which then migrate to the mesenteric lymph nodes (MLNs) to evoke specific T cell responses. In mouse models, Bif‐OVA‐Ocur effectively boosts the production of secretory immunoglobin A (SIgA) and promotes a strong mucosal and systemic immune response, leading to significant tumor suppression and resistance to tumor challenges. Importantly, the vaccine shows no systemic toxicity. This approach to harnessing the intestinal mucosal immune system offers valuable insights for the development of other non‐invasive oral vaccines and therapeutic agents.