Macrophage‐Targeted Isoniazid–Selenium Nanoparticles Promote Antimicrobial Immunity and Synergize Bactericidal Destruction of Tuberculosis Bacilli

Abstract Pathogenesis hallmarks for tuberculosis (TB) are the Mycobacterium tuberculosis (Mtb) escape from phagolysosomal destruction and limited drug delivery into infected cells. Several nanomaterials can be entrapped in lysosomes, but the development of functional nanomaterials to promote phagolysosomal Mtb clearance remains a big challenge. Here, we report on the bactericidal effects of selenium nanoparticles (Se NPs) against Mtb and further introduce a novel nanomaterial‐assisted anti‐TB strategy manipulating Ison@Man‐Se NPs for synergistic drug‐induced and phagolysosomal destruction of Mtb. Ison@Man‐Se NPs preferentially entered macrophages and accumulated in lysosomes releasing Isoniazid. Surprisingly, Ison@Man‐Se/Man‐Se NPs further promoted the fusion of Mtb into lysosomes for synergistic lysosomal and Isoniazid destruction of Mtb. Concurrently, Ison@Man‐Se/Man‐Se NPs also induced autophagy sequestration of Mtb, evolving into lysosome‐associated autophagosomal Mtb degradation linked to ROS‐mitochondrial and PI3K/Akt/mTOR signaling pathways. This novel nanomaterial‐assisted anti‐TB strategy manipulating antimicrobial immunity and Mtb clearance may potentially serve in more effective therapeutics against TB and drug‐resistant TB.