A Water‐Soluble Quercetin Conjugate with Triple Targeting Exerts Neuron‐Protective Effect on Cerebral Ischemia by Mitophagy Activation

Abstract The existing treatments for ischemic stroke cannot meet the clinical needs so far. Quercetin (QT) is an effective apoptosis inhibitor and antioxidant flavonoid, but its water solubility is poor and has no targeting. In this study, QT is modified with hyaluronic acid (HA) to form a water‐soluble conjugate HA‐QT, which can specifically bind to CD44 receptors and response to hyaluronidase. Next, a novel delivery system SS31‐HA‐QT is prepared by further modification with SS31, a polypeptide capable of penetrating the blood‐brain barrier (BBB) and indiscriminately targeting mitochondria. Meanwhile, IR780, a near‐infrared dye, is conjugated onto HA‐QT and SS31‐HA‐QT to form diagnosis tools to trace HA‐QT and SS31‐HA‐QT. In vitro and in vivo results shows that SS31 can four‐fold increase the drug penetration into BBB without any toxicity. The highly expressed CD44 and hyaluronidase in ischemic area ensured the targeted delivery of QT to the ischemic region. Importantly, the mitochondrial targeting of damaged neurons is also achieved by SS31. Further studies confirmed that SS31‐HA‐QT exerted neuron‐protection by activating mitophagy, and its mechanism involved Akt/mTOR related TFEB and HIF‐1 α activation. Hence, SS31‐HA‐QT shall be a promising neuroprotective drug due to its high water‐solubility, superior triple‐targeted neuroprotective ability, low toxicity, and high efficiency.