Mucoadhesive oral nanovaccine delivery system with immunomodulatory capacity for synergistic colorectal cancer therapy

Colorectal Cancer (CRC) remains a prevalent malignancy, with current chemotherapies limited by drug resistance, poor bioavailability, and severe toxicity. Although Cancer vaccines offer a promising alternative, their efficacy is constrained by inefficient tumor targeting and insufficient immune activation. Here, we present an oral nanovaccine delivery system (HML@HN) that integrates gastric protection, intestinal adhesion, tumor-specific delivery, and robust immune activation for enhanced CRC immunotherapy. The HML@HN nanovaccine is constructed by loading 5-FU-containing tumor cell lysate (TCL) into hollow manganese dioxide (HM) and co-coating with norepinephrine (NE) and hyaluronic acid (HA). The NE coating safeguards against gastric degradation while conferring mucoadhesive properties for prolonged intestinal retention, and HA enables active tumor targeting via CD44-mediated endocytosis. Upon internalization, the HM core responds to glutathione in the tumor microenvironment, triggering Mn²⁺ release and Reactive Oxygen Species (ROS) generation for chemodynamic therapy (CDT). This process, together with 5-FU, induces damage-associated molecular patterns (DAMPs), while the loaded TCL augments immunogenicity and the released Mn²⁺ promotes dendritic cell maturation. In an orthotopic CRC mouse model, oral HML@HN significantly suppresses tumor growth through these synergistic mechanisms. Collectively, this work presents a multifunctional oral nanovaccine that uniquely combines gastric protection, mucosal adhesion, tumor-responsive drug release, and potent immune activation for CRC immunotherapy.