2. Academic Validation
  3. Engineered endoplasmic reticulum-targeting nanodrugs with Piezo1 inhibition and promotion of cell uptake for subarachnoid hemorrhage inflammation repair

Engineered endoplasmic reticulum-targeting nanodrugs with Piezo1 inhibition and promotion of cell uptake for subarachnoid hemorrhage inflammation repair

  • J Nanobiotechnology. 2025 Apr 5;23(1):274. doi: 10.1186/s12951-025-03305-1.
Xiaojian Zhang # 1 2 3,  Enyan Jiang # 1 2 3,  Wangyang Fu 1 2 3,  Yuanyuan Wang 4 5,  Yiping Wang 1 2 3,  Zhen Fang 1 2 3,  Zichen Zhang 1 2 3,  Jiajia Duan 1 2 3,  Jia Zeng 1 2 3,  Yang Yan 6,  Fei Liu 7 8 9
Affiliations

Affiliations

  • 1 Department of Neurosurgery, The Fifth Affiliated Hospital of Sun Yat-Sen University, Zhuhai, 519000, Guangdong, People's Republic of China.
  • 2 Guangdong Provincial Engineering Research Center of Molecular Imaging, The Fifth Affiliated Hospital, Sun Yat-Sen University, Zhuhai, Guangdong, People's Republic of China.
  • 3 Guangdong-Hong Kong-Macao University Joint of Interventional Medicine, The Fifth Affiliated Hospital, Sun Yat-Sen University, Zhuhai, Guangdong, People's Republic of China.
  • 4 State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-Sen University Cancer Center, Guangzhou, 510060, People's Republic of China.
  • 5 Department of Medical Oncology, Sun Yat-Sen University Cancer Center, Guangzhou, People's Republic of China.
  • 6 Department of Neurosurgery, The Fifth Affiliated Hospital of Sun Yat-Sen University, Zhuhai, 519000, Guangdong, People's Republic of China. yanliuyuxia@163.com.
  • 7 Department of Neurosurgery, The Fifth Affiliated Hospital of Sun Yat-Sen University, Zhuhai, 519000, Guangdong, People's Republic of China. liuf235@mail.sysu.edu.cn.
  • 8 Guangdong Provincial Engineering Research Center of Molecular Imaging, The Fifth Affiliated Hospital, Sun Yat-Sen University, Zhuhai, Guangdong, People's Republic of China. liuf235@mail.sysu.edu.cn.
  • 9 Guangdong-Hong Kong-Macao University Joint of Interventional Medicine, The Fifth Affiliated Hospital, Sun Yat-Sen University, Zhuhai, Guangdong, People's Republic of China. liuf235@mail.sysu.edu.cn.
  • # Contributed equally.
PMID: 40186204 DOI: 10.1186/s12951-025-03305-1
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.

Keywords

Engineered endoplasmic reticulum; Intracranial hypertension; Piezo1; Subarachnoid hemorrhage.

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