cGAS-mediated antibacterial immunotherapy against tuberculosis by macrophage-targeted manganese dioxide nanoagonist

Tuberculosis (TB), induced by Mycobacterium tuberculosis (Mtb) infection, remains one of the top killers among infectious diseases. The pathogenesis hallmarks for TB are complex immune escape mechanisms of Mtb and low targeting effects of anti-TB drugs. cGAS signaling, which is responsible for triggering host antibacterial immunity against Mtb infection, has shown potentials to serve as targets for anti-TB immunotherapy. As cGAS agonist manganese ions (Mn²⁺) can activate cGAS-mediated autophagy to inhibit intracellular Mtb in macrophages, we constructed a functional nanoagonist targeting cGAS signaling based on manganese dioxide nanoparticles, naming Tuf-Rif@HA-MnO₂ NPs, for synergistic macrophage-targeted drug delivery and anti-TB immuno-therapeutics. Tuf-Rif@HA-MnO₂ NPs can actively target macrophages for rifampicin delivery and react with intracellular glutathione (GSH) to release Mn²⁺ for cGAS-STING signaling activation, which further promote autophagy and antibacterial M1 polarization of Mtb infected macrophages to achieve synergistic intracellular Mtb clearance. Furthermore, Tuf-Rif@HA-MnO₂ NPs can potentiate dendritic cell maturation, CD4+ Th1 cell and CD8+ cytotoxic T cell activation in vivo, which collectively attribute to reduced Mtb burdens and alleviated tissue inflammations in lung of Mtb-infected mice without systemic toxicity. This macrophage targeted drug delivery nanoagonist system is expected to develop rational immunotherapy strategy targeting cGAS signaling against TB and drug-resistant TB. STATEMENT OF SIGNIFICANCE: cGAS-mediated autophagy plays a critical role in Mtb clearance in macrophages. Tuf-Rif@HA-MnO₂ NPs specifically deliver rifampicin into macrophage for Mtb clearance. Tuf-Rif@HA-MnO₂ NPs activate cGAS-mediated macrophage autophagy for Mtb clearance. Tuf-Rif@HA-MnO₂ NPs synergize cGAS-mediated immunotherapy with targeted drug delivery for more effective anti-TB treatment.