Engineering a Nanoscale Al‐MOF‐Armored Antigen Carried by a “Trojan Horse”‐Like Platform for Oral Vaccination to Induce Potent and Long‐Lasting Immunity

Abstract Vaccination via the oral administration of an antigen faces many challenges, including gastrointestinal (GI) proteolysis and mucosal barriers. To limit GI proteolysis, a biomimetically mineralized aluminum‐based metal–organic framework (Al‐MOF) system that is resistant to ambient temperature and pH and can act synergistically as a delivery vehicle and an adjuvant is synthesized over a model antigen ovalbumin (OVA) to act as armor. To overcome mucosal barriers, a yeast‐derived capsule is used to carry the Al‐MOF‐armored OVA as a “Trojan Horse”‐like transport platform. In vitro experiments reveal that the mineralization of Al‐MOFs forms an armor on OVA that protects against highly acidic and degradative GI conditions. However, the mineralized Al‐MOFs can gradually disintegrate in a phosphate ion‐containing simulated intracellular fluid, slowly releasing their encapsulated OVA. In vivo studies reveal that the “Trojan Horse”‐like transport platform specifically targets intestinal M cells, favoring the transepithelial transport of the Al‐MOF‐armored OVA, followed by subsequent endocytosis in local macrophages, ultimately accumulating in mesenteric lymph nodes, yielding long‐lasting, high‐levels of mucosal S‐IgA and serum IgG antibodies. Such an engineered delivery platform may represent a promising strategy for the oral administration of prophylactic or therapeutic antigens for vaccination.