IL-15 functionalized biomimetic hybrid mRNA vaccine for enhanced NSCLC immunotherapy via synergistic activation of T cells and NK cells

CD8⁺T cells-based mRNA vaccines represent a promising strategy for cancer immunotherapy. However, their development is significantly limited by the low-expression of major histocompatibility complex (MHC) I on tumor cells, which impairs effective antigen presentation and T cells recognition. Given that natural killer (NK) cells can kill tumors in an MHC-independent manner, dual activation of T cells and NK cells has the potential to enhance the efficacy of immunotherapy. Herein, we developed an IL-15 functionalized biomimetic hybrid mRNA vaccine (LMPR) that activates NK cells in collaboration with CD8⁺T cells, compensating the MHC-dependent limitation to boost antitumor therapy. Once vaccinated, LMPR is effectively taken up by dendritic cells (DCs) and successfully translated into antigenic proteins to initiate antigen-specific T-cell immune responses. Meanwhile, IL-15/IL-15 receptor α (IL-15Rα) induces oxidative stress tolerance of NK cells by regulating the balance of thioredoxin system, thereby promoting the proliferation of NK cells and synergistically exerting anti-tumor effect with CD8⁺T cells. Upon intranasal administration to lewis lung cancer (LLC) -bearing mice, LMPR signifcantly promotes infiltration of CD8⁺T cells and NK cells, accompanied by elevated level of interferon-γ (IFN-γ) and Granzyme B (GZMB), exhibiting superior cytotoxicity in suppressing tumor growth. Notably, LMPR potently facilitates the up-regulation of T-bet, thus enriching the differentiation of effector memory T cell (Tem) to inhibit tumor recurrence. Therefore, this innovative approach elicits dual activation by CD8⁺T cells and NK cells, holding great potential for potentiating therapeutic mRNA vaccination antitumor immunity.