Exosomal co-delivery of CircRNA-TRAPPC6B and rifampicin for enhanced immunotherapy against tuberculosis

Tuberculosis (TB), a highly lethal infectious diseases induced by Mycobacterium tuberculosis (Mtb) infection, continues to be a major challenge in the realm of infectious diseases. Functional circular RNAs (circRNAs) have been extensively reported to play crucial immunological regulatory roles in Mtb infection and TB development. Our previous researches have demonstrated that CircRNA TRAPPC6B (circTRAPPC6B) can enhance autophagy in Mtb infected macrophages to facilitate intracellular Mtb inhibition/clearance, while how to expand the potential of circTRAPPC6B for effective anti-TB treatment remains a considerable challenge. Here, we innovated a novel macrophage-targeted exosome system, designated as Man-Rif@CircRNA@Exo, which encapsulates circTRAPPC6B and rifampicin to synchronize targeted antibiotic killings and host immunological defenses against Mtb. Man-Rif@CircRNA@Exo exhibited selective macrophage targeting effects attributable to mannose modification and then accumulated into lysosomes of macrophages. Furthermore, Man-Rif@CircRNA@Exo treatment significantly increased intracellular circTRAPPC6B level, which in turn promoted autophagy of Mtb infected macrophages, thereby accelerating host immunological clearance of Mtb. Collectively, Man-Rif@CircRNA@Exo indicated enhanced intracellular Mtb killing efficiency by synergizing targeted rifampicin bacteriocidal action with autophagy-mediated host immunological clearance against Mtb. This synergistic anti-TB approach significantly reduced Mtb burdens and alleviated tissue pathology and inflammation in the lungs of Mtb-infected mice, without significantly affecting liver/kidney structure and functional parameters to show acceptable safety. These results highlight the promising potential of Man-Rif@CircRNA@Exo to synchronize targeted antibiotic action and host immunological defenses for more effective anti-TB treatment, which is anticipated to advance the development of novel host directed therapeutics against TB and drug-resistant TB.