Dual-functional pH-sensitive nanoliposomes modified with CD47 mimicry peptide enhance icariin delivery to attenuate neuroinflammation and oxidative stress in epilepsy

Around 30 % of patients fail to achieve seizure-free with existing anti-seizure medications (ASMs), and developing drugs that target neuroinflammatory and oxidative stress may benefit patients with refractory epilepsy. The bioactive compound icariin (ICA) isolated from the traditional Chinese medicine Epimedium has strong anti-inflammatory and antioxidant effects. Nonetheless, the clinical application of ICA is restricted by its low bioavailability and limited ability to penetrate the blood-brain barrier (BBB). This research developed a pH-sensitive nanoliposome delivery system modified with CD47 mimicry peptide(ICA@LipD-CD47) to enhance the therapeutic efficacy of ICA for epilepsy. Through the immune escape mechanism of CD47 mimicry peptide, the phagocytosis of the drug-loaded nanoparticles by macrophages could be reduced, thereby facilitating the prolonged circulation of ICA. Additionally, considering the acidic microenvironment present in the epileptogenic foci, pH-sensitive liposomes could enhance the efficiency of ICA's targeted entry into the epileptogenic foci. In this study, network pharmacology, animal experiments, and transcriptomics analysis confirmed the effect of ICA in alleviating epilepsy-induced inflammation and oxidative stress. Moreover, ICA@LipD-CD47 demonstrated prolonged circulation and effective targeting of epileptogenic foci, significantly alleviating neuronal damage and cognitive dysfunction in epileptic mice. As a novel nano-delivery system, ICA@LipD-CD47 presents a promising approach to improve the therapeutic effectiveness of ICA for treating epilepsy.