Abstract
Curing tuberculosis (TB) remains challenging due to treatment complexity and high recurrence rates. Through bioinformatic analyses of the immune microenvironment within clinical non-tuberculous granulomas (NTBG)/tuberculous granulomas (TBG) samples, and peripheral blood from drug-resistant/sensitive, recurrent/non-recurrent TB patients, we identify suppression of innate immune responses, especially downregulated Toll-like receptor/NF-kappa B pathways in macrophages/dendritic cells and elevated B/T cell negative regulation, contributing to treatment failure and recurrence. Building on these insights, we develop mannose-modified organic semiconducting nano-immunostimulants ((man)SNI) for precise TB sono-immunotherapy. Under optimized ultrasound condition, (man)SNI generates massive reactive oxygen species (ROS) to eradicate Mycobacterium tuberculosis (M.tb) within lung granulomas/macrophages, while simultaneously promoting in situ release of M.tb-derived antigens. The released antigens and TLR7 agonist R837 synergistically induce potent innate/adaptive anti-TB immunity and long-lasting immune memory. This granulomas microenvironment-guided sono-immunotherapy strategy demonstrates efficient TB control and relapse/reinfection prevention, which provides a promising direction for customized therapy against high-pathogenic infections.