Macrophage targeted cellular microparticles synergize anti-tuberculosis therapy combining CircRNA-mediated host immune defense and antibiotic killing

Tuberculosis, caused by <i>Mycobacterium tuberculosis</i> (Mtb) infection, remains one of the most deadly infectious diseases worldwide. There is an urgent need for the development of innovative strategies improving the antibiotic efficiency and enhancing host immunological defenses for more effective TB treatment. CircRNA TRAPPC6B (circTRAPPC6B) can enhance autophagy and M1 polarization of Mtb infected macrophages to facilitate intracellular Mtb clearance, arising the promise for more effective anti-TB treatment. Here, we innovated macrophage targeted cellular microparticles encapsulating circTRAPPC6B and rifampicin inside to synergize targeted drug killing and enhanced host immunological clearance, thereby providing more effective anti-TB treatment to optimize therapeutic outcomes. The engineered Gal-CircRNA@Rif@MPs nanosystem showed selective macrophage targeting effects due to galacose surface functionalization and could significantly increase intracellular circTRAPPC6B levels, thereby promoting autophagy and anti-bacterial polarization of Mtb infected macrophages. Collectively, Gal-CircRNA@Rif@MPs demonstrated enhanced intracellular Mtb killing efficiency by synergizing targeted rifampicin action and antibacterial host immune defenses, thus significantly reducing Mtb burdens and alleviating lung tissue pathology in Mtb-infected mice without notable toxicity. Our findings demonstrate, for the first time, that circRNAs with immunomodulatory properties can be effectively combined with anti-TB drugs using cellular microparticles to achieve host cell-targeted Mtb clearance with alleviated pathology and acceptable toxicity profiles. These results introduce the potentials of Gal-CircRNA@Rif@MPs as novel host cell targeted system to synchronize selective antibiotic actions and host immunological defenses for more effective anti-TB treatment, advancing novel therapeutics against TB.