Self-assembled polysaccharide nanoparticles enable M cell–mediated oral immune entry and enhance systemic antitumor immunity

Oral delivery of immunomodulators offers a non-invasive strategy for sustained immune intervention, yet its application to macromolecular agents remains limited by the lack of defined immune entry pathways. In particular, whether orally administered biomacromolecules can access organized intestinal lymphoid tissues and contribute to systemic immunity remains poorly understood. Here, we report a structure-guided polysaccharide assembly (COS@GP) that enables pathway-defined oral immune entry via M cell–mediated transcytosis into Peyer’s patches. The co-assembled architecture maintains structural integrity under gastrointestinal conditions while promoting coordinated cellular uptake. Using an in vitro M-cell model and in vivo analysis, COS@GP exhibits enhanced trans-epithelial transport and preferential accumulation within intestinal lymphoid tissues. At the biological level, COS@GP induces a controlled mucosal immune activation characterized by the upregulation of innate immune pathways without excessive inflammatory responses. This localized priming facilitates downstream immune propagation and enhances systemic antitumor immunity when combined with radiotherapy. Collectively, this study establishes a structure-function framework in which polysaccharide assemblies are engineered not only for delivery, but for defining immune entry pathways, providing a foundation for oral immunomodulatory strategies.