18β-Glycyrrhetinic Acid-Loaded ROS-Responsive Liposomes Enhance the Neuroprotective Efficacy against Cerebral Ischemic Stroke in Mice via a Microenvironment-Responsive Strategy.

18β-Glycyrrhetinic acid (GA) exhibits excellent anti-inflammatory and antioxidant activities, and has attracted considerable attention in the field of cerebral ischemia-reperfusion (I/R) injury therapy. However, it is plagued by problems of low bioavailability and dose-dependent toxicity. As a drug delivery platform for the treatment of ischemic stroke, microenvironment-responsive liposomes can cross the impaired blood-brain barrier, efficiently deliver drugs to the lesion sites, and improve therapeutic efficacy. Herein, to address the challenges posed by the highly oxidative-stress microenvironment of I/R and the intrinsic physicochemical properties of GA, we encapsulated GA into liposomes and incorporated thioketal (TK) linkages into the phospholipid bilayer to fabricate GA@TK-Lip. GA@TK-Lip can effectively target damaged neurons, attenuate neuroinflammation, scavenge excessive ROS, ameliorate cellular oxidative stress via the Nrf2/HO-1 pathway, reduce neuronal apoptosis and cerebral infarct volume to 43.2% and 23.3% of that in the MCAO group, and restore neurological function. Collectively, this study provides novel insights into the development of promising therapeutic strategies for ischemic stroke.