Intranasal delivery of LB244-loaded M2 microglia membrane nanoparticles for targeted treatment of neuroinflammation after I/R brain injury

Ischemic stroke following revascularization therapy inevitably leads to varying degrees of ischemia/reperfusion (I/R) injury. The complexity of post-I/R inflammatory processes have hindered the development of effective strategy to improve functional recovery in stroke patients. Extensive evidence has confirmed that activation of the STING pathway and microglial pyroptosis exacerbates neuroinflammatory responses and neuronal damage in cerebral I/R injury. LB244, a potent STING inhibitor, shows therapeutic promise but suffers from poor solubility and bioavailability. Here, we developed LB244@M2 nanoparticles by encapsulating LB244 in M2 microglia membrane vesicles. Intranasal administration of LB244@M2 enabled direct nose-to-brain delivery, achieving 1.7-fold higher brain accumulation than intravenous injection within 2 h. By inhibiting the STING pathway, LB244@M2 attenuated pyroptosis-induced microglial inflammation and promoted the phenotypic shift from pro-inflammatory (M1) to anti-inflammatory (M2) states. This conferred significant neuroprotection, reducing neuroinflammatory cell death by 67.9 % and infraction volume by 49.8 % compared to saline-treated controls. Moreover, LB244@M2-treated I/R mice exhibited 53.3 % improvement in Bederson neurological score at 7 days post-treatment, with no observed adverse effects. These findings highlighted LB244@M2 as a promising nanotherapeutic strategy to mitigate neuroinflammation and enhance post-stroke recovery.