Granulomas microenvironment-guided sono-immunotherapy to treat and prevent recurrence of tuberculosis

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 (^manSNI) for precise TB sono-immunotherapy. Under optimized ultrasound condition, ^manSNI 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.