A pH-responsive guanidino-based covalent organic framework nanodrugs for enhanced neuroprotection against subarachnoid hemorrhage by targeting NLRP3 inflammasome

Abstract

Subarachnoid hemorrhage (SAH) represents a severe subtype of stroke, distinguished by its substantial mortality and morbidity rates. It initiates a series of harmful physiological responses, such as increased intracranial pressure, cerebral edema, and neuroinflammation. Pyroptosis, a form of cell death dependent on caspase-1, plays a crucial role in the inflammatory processes following SAH. Recent research indicated that the inhibition of the NLRP3 inflammasome is regarded as a promising therapeutic strategy for mitigating inflammatory responses. Bindarit, a β-blocker with anti-inflammatory properties, has demonstrated potential in mitigating NLRP3-mediated pyroptosis. Nevertheless, its clinical application is limited by its short half-life and inadequate penetration of the blood-brain barrier (BBB). To address these limitations, a novel pH-responsive erythrocyte membrane-biomimetic guanidino-based covalent organic framework (COF) nanocarrier, designated as B@COF_DT-R, has been developed to encapsulate bindarit. This nanocarrier is specifically engineered to enhance drug delivery across the BBB and target the NLRP3/Caspase-1/GSDMD axis, thereby inhibiting neuronal pyroptosis in vitro and vivo. The development of B@COF_DT-R constitutes a substantial advancement in the treatment of SAH. Through the enhancement of drug delivery mechanisms and the targeted modulation of critical inflammatory pathways, this nanocarrier holds the potential to significantly improve therapeutic outcomes for patients suffering from SAH.