Orally activatable membrane fusion-mitochondria hitchhiking on intestinal macrophages for targeted therapy of bacterial meningitis and neuroinflammation.

Targeting the formidable physiological barriers and neuronal damage refractory to conventional bactericidal agents for bacterial meningitis, we engineered an infection microenvironment-activatable membrane fusion-mitochondrial formulation (Mito@MFL-Glu). This formulation integrates endogenous macrophage hitchhiking, lysosomal exocytosis-driven cargo release, and in situ mitochondrial transplantation. Orally administered, its glucan shell is recognized by microfold cells, enabling macrophage-mediated transport across the blood-brain barrier and chemotactic accumulation at infectious foci. During macrophage uptake, stimulation of the Dectin-1 by the glucan shell sustains intracellular Ca2+ levels. Upon reaching the infectious lesion, the pro-inflammatory microenvironment induces macrophage polarization toward an M1 phenotype, which further elevates intracellular Ca2+ levels. The synergy of these two sequential Ca2+ concentration events cooperatively triggers TFEB-mediated lysosomal exocytosis, resulting in a cargo efflux efficiency of 43.3%. Elevated local reactive oxygen species (ROS) cleave the ROS-responsive linker, detaching the glucan shell and exposing the fusogenic lipid bilayer. This activated layer then directly fuses with damaged neuron and microglial membranes, delivering exogenous mitochondria into the cytosol while bypassing lysosomal degradation and achieving a transplantation efficiency exceeding 36% within 1 h, whereas naked mitochondria show much lower efficiency. Concurrently, the liberated cefotaxime eliminates pathogens, culminating in a synergistic and non-invasive oral closed-loop bactericidal and neuroreparative strategy in a murine meningitis model.