Biomimetic stress granules replenish lysosomal repair to reinstate macrophage immunometabolic antibacterial programs.

Abstract

Severe intracellular bacterial infection can progressively compromise lysosomal defence in macrophages, yet the underlying repair bottleneck remains unclear. Here we identify a time-dependent exhaustion of stress granule (SG)-associated lysosomal repair during sustained infection: progressive depletion of core SG components, including G3BP1 and galectin-3 (Gal-3), undermines lysosomal membrane resealing, resulting in lysosomal deacidification and persistent cytosolic acidification. This pH imbalance suppresses glycolytic metabolism and blunts macrophage pro-inflammatory antibacterial programs, thereby enabling intracellular bacterial persistence. Since this exhausted repair module cannot be readily reconstituted by conventional pharmacological or genetic approaches, we engineer biomimetic stress granules (BSGs), Gal-3-functionalized nanodiscs cloaked in acid-responsive fusogen-expressing macrophage membrane vesicles (Gal3-NDs@EF-MNVs), to achieve sequential targeting and cytosolic delivery to damaged lysosomes. BSGs stabilize membrane lesions, suppress lysosomal leakage and restore lysosomal acidification, pH homeostasis and metabolic fitness, thereby recapitulating the 'plugging' behavior of native stress granules at sites of membrane injury. This work establishes biomimetic organelle repair as a general, materials-driven paradigm to restore innate immunity against intracellular infections - without escalating antibiotics or genetic manipulation.