pH-Responsive β-Glucans-Complexed mRNA in LNPs as an Oral Vaccine for Enhancing Cancer Immunotherapy

mRNA vaccines for cancer immunotherapy are commonly delivered using lipid nanoparticles (LNPs), which, when administered intravenously, may accumulate in the liver, potentially limiting their therapeutic efficacy. To overcome this challenge, the study introduces an oral mRNA vaccine formulation tailored for efficient uptake by immune cells in the gastrointestinal (GI) tract, known for its high concentration of immune cells, including dendritic cells (DCs). This formulation comprises mRNA complexed with beta-glucans (beta Glus), a potential adjuvant for vaccines, encapsulated within LNPs (beta Glus/mRNA@LNPs). The beta Glus/mRNA complexes within the small compartments of LNPs demonstrate a distinctive ability to partially dissociate and reassociate, responding to pH changes, effectively shielding mRNA from degradation in the harsh GI environment. Upon oral administration to tumor-bearing mice, beta Glus/mRNA@LNPs are effectively taken up by intestinal DCs and local nonimmune cells, bypassing potential liver accumulation. This initiates antigen-specific immune responses through successful mRNA translation, followed by drainage into the mesenteric lymph nodes to stimulate T cells and trigger specific adaptive immune responses, ultimately enhancing antitumor effects. Importantly, the vaccine demonstrates safety, with no significant inflammatory reactions observed. In conclusion, the potential of oral beta Glus/mRNA@LNPs delivery presents a promising avenue in cancer immunotherapy, offering needle-free and user-friendly administration for widespread adoption and self-administration. Upon oral administration of beta Glus/mRNA@LNPs, the pH-responsive partial dissociation/reassociation behavior of beta Glus/mRNA complexes within LNPs effectively shields mRNA from degradation in the harsh gastrointestinal (GI) environment. beta Glus serve as both a protective agent and an adjuvant, facilitating stable delivery into GI-resident dendritic cells and non-antigen presenting cells for translation into tumor-associated antigens. This process initiates antigen-specific immune responses against tumors. image