Catch-to-Amplify Nanoparticles with Bacteria Surface for Sequential Mucosal Immune Activation for Acute Myeloid Leukemia Therapy.

Abstract

Mucosal-mediated immune deficiency is associated with immune evasion and poor clinical outcomes in acute myeloid leukemia (AML). Here, we describe the elicitation of mucosal and systemic immune response by oral delivery of MDP-modified PEG-lipid (MDP-PEG-DSPE) and polylactic acid-polyhistidine (PLA-PHis) copolymer constructed nanosystem (mPOD) into Peyer's patches. To protect against gastrointestinal degradation, enteric-soluble capsules are utilized for encapsulating mPOD to promote penetration across intestinal mucus and engender robust Peyer's patch targeting initiated by MDP-PEG-DSPE. Compared with intravenous and intramuscular administration, the oral delivery of MDP-PEG-DSPE and 5'-triphosphate-modified RNA (ppp-RNA) into gut-associated lymphoid tissues reinforces dendritic cell maturation and migration, amplifies mucosal immune response, and boosts the production of secretory immunoglobulin A via retinoic acid-inducible gene I/nucleotide-binding oligomerization domain 2 (RIG-I/NOD2) signaling activation. In the AML murine model, the provoked mucosal immunity positively regulates the systemic cytotoxic immune reactions, which, in turn, eradicate disseminated malignant leukemic cells and provide defense against leukemia attacks.