Hybrid Bacterial Membrane Nanovaccine Reprograms the Tuberculosis Immune Microenvironment via CD40 to Surpass BCG Protection
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Tuberculosis (TB) remains a leading cause of death worldwide, partly because current vaccines provide limited protection against adult pulmonary disease. This limitation is associated with ineffective antigen presentation and immune tolerance induced by Mycobacterium tuberculosis (Mtb). To address this challenge, we developed ME-NPs, a biomimetic nanovaccine composed of a poly (lactic-co-glycolic acid) core cloaked with a hybrid membrane derived from Mtb inner membranes and Escherichia coli membranes, enabling coordinated delivery of antigens and immunostimulatory signals. In mice, ME-NPs efficiently trafficked to draining lymph nodes and sustained dendritic cell (DC) activation. Single-cell transcriptomic analysis showed that, unlike BCG, ME-NPs reprogrammed the immune microenvironment and preferentially induced a “licensed” DC phenotype characterized by upregulation of Cd40 and Irf1 . Functional blockade assays identified the CD40–CD40L axis as a critical checkpoint for T cell priming, promoting Th1-polarized memory-like T cell differentiation and enhancing macrophage bactericidal activity. Accordingly, ME-NPs conferred superior protection against aerosol Mtb challenge, significantly reducing pulmonary bacterial burden and tissue pathology compared to BCG. These findings demonstrate that hybrid membrane-based immune reprogramming can overcome Mtb-induced immune tolerance and provide a rational strategy for developing next-generation TB vaccines.
