Hemoglobin-corona nanomedicine for precise granulomas host-directed dual-modulation to enhance chemotherapy of late-stage tuberculosis

Early-stage tuberculosis (TB) can be effectively managed with standardized chemotherapy, while the late-stage TB presents significant therapeutic challenges due to the complex pathological features of its granulomas, resulting in significantly high treatment failure and recurrence rates. Elucidating the impact of the microenvironment of late-stage granulomas on therapy and developing precise targeted strategies are the keys to treating late-stage TB. This study conducted the comprehensive multi-dimensional analysis to compare early- vs. late-stage granuloma microenvironments, identifying two core obstacles to effective treatment of late-stage TB: (1) M2 macrophages dominate the immunosuppressive microenvironment of late-stage granulomas, while also serving as the primary reservoir for Mycobacterium tuberculosis (Mtb); (2) long-term hypoxia of bacterial-colonized macrophages lead to the heightened chemoresistance of Mtb in late-stage TB. Targeting these two core obstacles, we developed a hemoglobin (Hb)-corona nanomedicine platform termed HbLip@RH to target co-deliver rifampicin Rif (Rif, first-line anti-TB chemotherapy), hydroxychloroquine (HCQ, an M2 macrophage reprogrammer), and molecular oxygen (hypoxia alleviator) to granuloma-associated M2 macrophages for late-stage TB treatment. HbLip@RH can specifically targets granuloma-associated M2 macrophages via the Hb-haptoglobin-CD163 pathway, precisely reprograms M2 to pro-inflammatory M1 phenotypes to alleviate immunosuppression, and alleviates hypoxia to reactivates dormant Mtb, thereby restoring antibiotic sensitivity of Mtb. In murine tail/orthotopic and zebra fish late-stage TB models, HbLip@RH achieves complete bacterial clearance. This work not only elucidates the pathological mechanisms of late-stage TB but also provides a transformative host-directed dual modulation strategy with chemotherapy to overcome late-stage TB refractoriness, providing a promising approach for late-stage TB.