Targeted microglial ROS-scavenging alleviates neuroinflammation and cognitive deficits via restoration of the 2-AG/CB2R signaling axis in schizophrenia

Cognitive impairment in schizophrenia is inadequately treated. The molecular link between oxidative stress and neuroinflammation in its pathophysiology remains unclear. We measured CB2R in circulating microglia‑derived exosomes from schizophrenia patients and healthy controls. In a maternal separation rat model, we assessed brain reactive oxygen species, microglial activation, and the 2‑AG/CB2R signaling axis. A microglia‑targeted hydrogen‑releasing nanoplatform (PdH 0.12 @CM) was administered to maternal separation rats, followed by behavioural, histological and transcriptomic analyses. In primary microglia, we examined the effects of hydrogen peroxide on CB2R, 2‑AG and inflammatory responses, and tested rescue with a CB2R agonist or exogenous 2‑AG. CB2R was reduced in patient-derived microglia exosomes and correlated with cognitive performance and symptom severity. Maternal separation rats showed elevated brain reactive oxygen species, microglial activation, and selective decreases in microglial 2-AG and CB2R, with reduced CB2R expression observed in the hippocampal CA1 region. PdH 0.12 @CM treatment scavenged reactive oxygen species, restored 2‑AG/CB2R signaling, suppressed pro‑inflammatory cytokines, and rescued cognitive and sensorimotor deficits. In vitro, hydrogen peroxide directly reduced CB2R and 2‑AG levels, increased CD86 and cytokine release; these effects were reversed by a CB2R agonist or 2‑AG. Elevated oxidative stress is associated with disruption of the microglial 2‑AG/CB2R axis, which correlates with neuroinflammation and cognitive deficits. Targeted ROS scavenging restores this pathway, identifying the 2‑AG/CB2R axis as a potential therapeutic target in schizophrenia.