This study provides multi-omics evidence for autophagy modulation mediated by the exosomal nucleic acid delivery system, verifies that this system regulates macrophage autophagy by controlling the TLR4-NF-κB pathway and AMPK/mTOR pathway, and clarifies the application potential of this system in tuberculosis (TB) and other macrophage-associated. Here, TLR4 is linked to tuberculosis.