Mitochondria-targeting urolithin A/borneol nanoparticles: enhanced therapeutic effects for cerebral ischemia–reperfusion injury in rats

Urolithin A (UA), a metabolite of ellagitannins produced by gut microbiota, exhibits a range of beneficial biological activities, particularly its ability to promote mitophagy, indicating its potential for treating ischemic stroke. However, its therapeutic efficacy is limited by poor solubility. In this study, we developed triphenylphosphonium (TPP)-modified UA nanoparticles, utilizing DSPE-PEG as a stabilizer and co-loading borneol (BO) as a permeation enhancer. The resultant UA-BO-TPP-NPs exhibited an average particle size of 172.2 nm, a zeta potential of −2.24 mV, and a substantial drug payload of 39.52%. UA-BO-TPP-NPs demonstrated commendable stability in diverse physiological media and during storage. In vitro experiments showed that UA-BO-TPP-NPs significantly enhanced cellular uptake and achieved high mitochondrial co-localization under both normal conditions and oxygen-glucose deprivation/reoxygenation (OGD/R) conditions. UA-BO-TPP-NPs markedly reduced intracellular reactive oxygen species (ROS) and malondialdehyde (MDA) levels while increasing adenosine triphosphate (ATP) content in human brain microvascular endothelial cells (HBMEC) and SH-SY5Y cells. Furthermore, intravenously injected UA-BO-TPP-NPs effectively accumulated in the brains of rats after cerebral ischemia–reperfusion (I/R) compared to conventional UA-NPs. Consistently, UA-BO-TPP-NPs significantly reduced brain infarction, increased survival rates, preserved blood–brain barrier (BBB) integrity, inhibited oxidative stress, and ameliorated neurological function in cerebral I/R rats. In summary, UA-BO-TPP-NPs effectively delivered encapsulated UA to mitochondria and demonstrated superior therapeutic efficacy in cerebral I/R rats, highlighting the potential for treating ischemic stroke.