A dual-site oral nanovaccine programs anti-colorectal tumor immunity from small intestinal priming to large intestinal boosting.

Oral vaccines hold great promise for colorectal cancer (CRC) immunotherapy but are limited by inefficient mucosal delivery and a lack of spatiotemporal control over immune activation. Here we report a spatiotemporally programmed oral nanovaccine that implements a dual-site vaccination strategy through a sequential and causally linked immune cascade, initiating immune priming in Peyer's patches of the small intestine and subsequently amplifying immunity at colorectal tumor sites. The nanovaccine (DPML@OVA-CpG), composed of antigen- and CpG-loaded mesoporous polydopamine nanoparticles stabilized by β-glucan and plant-derived lipids, resists gastrointestinal degradation and targets gut-associated lymphoid tissues. Following oral administration, it induces robust systemic effector and memory T cell responses via small intestinal priming, while a fraction traffics to colorectal tumors. There, near-infrared irradiation triggers immunogenic cell death of tumor cells and, together with locally released CpG, converts tumors into autologous in situ vaccine factories. This spatiotemporally orchestrated strategy achieves potent therapeutic efficacy against liver metastatic CRC, extending survival compared to PD-L1 antibody therapy and traditional single-site oral vaccination.