Host-directed nanotherapy for the treatment and imaging of tuberculous meningitis

Rationale: Tuberculous meningitis (TB meningitis) is a devastating infection where the host immune response drives brain injury.Standard adjunctive corticosteroids often fail to prevent neurological sequelae or improve survival in many populations.Host-directed therapies that can cross the blood-brain barrier (BBB) and reduce neuroinflammation are urgently needed.We evaluated a hydroxyl-terminated polyamidoamine (PAMAM) dendrimer as a theranostic nanoplatform to visualize and treat microglia-mediated neuroinflammation in a young rabbit model of TB meningitis.Methods: A novel radiolabeled dendrimer ( 124 I-dendrimer) was synthesized for noninvasive positron emission tomography (PET) imaging, with post-mortem gamma counting and fluorescent-labeled dendrimer (D-Cy5) confirming biodistribution.For therapy, rabbits with TB meningitis (i.e., infected) received weekly intravenous dendrimer-N-acetyl cysteine (D-NAC) or phosphate buffered saline (PBS).After two weeks, treatment efficacy was evaluated with longitudinal neurobehavioral scores and multimodal PET ( 18 F-FDG for glucose metabolism, 18 F-py-albumin for BBB integrity, and 124 I-DPA-713 for microglial/macrophage activation).Post-mortem analyses included bacterial burden (colony-forming units [CFU]), cerebrospinal fluid (CSF) protein and cytokine levels, and brain immunohistochemistry for glial and white matter markers.Results: 124 I-Dendrimer demonstrated selective accumulation within brain lesions, co-localizing primarily with activated microglia.D-NAC significantly improved neurological outcomes and attenuated neuroinflammation and brain injury, even without antimicrobial therapy.Longitudinal PET imaging confirmed D-NAC efficacy, showing decreased neuroinflammation ( 124 I-DPA-713) and improved BBB integrity ( 18 F-py-albumin).Post-mortem analyses corroborated these findings, demonstrating that D-NAC reduced microglial inflammation and IL-17a levels, while improving myelination and BBB integrity.Conclusions: This study establishes D-NAC as a promising host-directed theranostic strategy for TB meningitis and supports the clinical potential of dendrimer nanoplatforms to diagnose and treat central nervous system infections.