Quercetin-loaded zeolitic imidazolate framework-8 nanoparticles through borneol-embedded hyaluronic acid hydrogel for ischemic stroke treatment.

Ischemic stroke (IS), widely known for the frequency and the high disability rate, remains challenging to conquer due to its complex pathology. The therapeutic application of Quercetin (QC), a natural flavonoid with powerful antioxidant and anti-inflammatory activities, its therapeutic application is limited by low bioavailability，and so is the blood-brain barrier (BBB)，with a major obstacle in the effective delivery of drugs to the brain. In view of the above, this study aimed to develop an intranasal administration (IN) system based on borneol (Bo) embedded thermosensitive hydrogel, to deliver QC-loaded zeolite imidazolate framework-8 (ZIF-8) nanoparticles (QC@ZIF-8 NPs) for the synergistic treatment of IS. Up to now, QC@ZIF-8 NPs with uniform particle size and pH-responsive release characteristics has been successfully synthesized. And with its ideal property of temperature-sensitivity, bio-compatibility and release-sustainability, the prepared Bo/QC@ZIF-8-Gel was evaluated through in vitro experiments (MTT, LDH, ROS, JC-1, immunofluorescence, ELISA) to test its neuro-protective, anti-inflammatory, and antioxidant properties. The results showed that Bo/QC@ZIF-8-Gel effectively scavenged ROS, attenuated OGD/R-induced cell damage, and significantly lowered the levels of pro-inflammatory factors (TNF-α, IL-1β, IL-6) by promoting microglial polarization from the pro-inflammatory M1 phenotype to the anti-inflammatory M2 phenotype. Besides, pharmacokinetic studies in rats showed that borneol significantly promoted drug enrichment in the brain following the IN of this gel system. Furthermore, in a rat model of the middle cerebral artery occlusion (MCAO), we evaluated the brain targeting of Bo/QC@ZIF-8-Gel (via in vivo imaging), as well as its effects on the cerebral infarct volume and the neurological function. The results showed that Bo/QC@ZIF-8-Gel treatment significantly reduced the cerebral infarct volume, improved the neurological function scores, increased the number of surviving neurons, effectively inhibited the inflammatory response in the brain, and promoted the neurological recovery in MCAO model rats. In summary, Bo/QC@ZIF-8-Gel represents a promising strategy for the treatment of IS.