Engineered endoplasmic reticulum-targeting nanodrugs with Piezo1 inhibition and promotion of cell uptake for subarachnoid hemorrhage inflammation repair
Xiaojian Zhang, Enyan Jiang, Wangyang Fu, Yuanyuan Wang, Yiping Wang, Zhen Fang, Zichen Zhang, Jiajia Duan, Jia Zeng, Yan Yang, Fei Liu
Abstract
Subarachnoid hemorrhage (SAH) is a life-threatening acute hemorrhagic cerebrovascular condition, often presenting with severe headaches caused by intracranial hypertension, which in severe cases can lead to brain herniation. Piezo1 is a mechanosensitive ion channel protein whose mechanical properties are closely linked to central nervous system diseases. In this study, we developed an engineered endoplasmic reticulum membrane-based nanomedicine (CAQKERM@GsMTx4) using HEK293T cells, aimed at targeted delivery to acute hemorrhagic regions, rapid absorption, and precise inhibition of Piezo1 therapy. To ensure optimal targeting and therapeutic efficacy, we fused the CAQK peptide gene to the N-terminus of TRP-PK1, presenting the CAQK peptide on the endoplasmic reticulum membrane, and loaded GsMTx4 into engineered vesicles (EVs) derived from this engineered membrane. Through in vivo and in vitro experiments and multi-omics analysis, we have demonstrated the marked advantages of endoplasmic reticulum membrane vesicles over cell membrane-based vesicles. CAQKERM@GsMTx4 successfully inhibits Piezo1 in SAH, helps microglia change from the M1 phenotype to the M2 phenotype, and inhibits inflammatory responses and neuronal damage. Overall, this novel engineered endoplasmic reticulum membrane nanomedicine provides a potential effective strategy for the clinical treatment of subarachnoid hemorrhage. Engineered endoplasmic reticulum membrane-based nanomedicine, CAQKERM@GsMTx4, specifically targets hemorrhagic regions in subarachnoid hemorrhage (SAH). By inhibiting the Piezo1 ion channel, it promotes M2 microglial transformation, reducing inflammation and neuronal damage. This innovative approach leverages targeted delivery and precise modulation, offering a promising strategy for SAH treatment in both in vitro and in vivo models.