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Bioengineered nanovesicles for efficient siRNA delivery through ligand-receptor-mediated and enzyme-controlled membrane fusion

Lele Cui, Yongsheng Cui, Jing Liu, Wei Li, Mengdan Wu, Xiawei Wei, Ying Lai () and Peng Mi ()
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Lele Cui: Sichuan University
Yongsheng Cui: Sichuan University
Jing Liu: Sichuan University
Wei Li: Sichuan University
Mengdan Wu: Sichuan University
Xiawei Wei: Sichuan University
Ying Lai: Sichuan University
Peng Mi: Sichuan University

Nature Communications, 2025, vol. 16, issue 1, 1-20

Abstract: Abstract A major obstacle in knocking down oncogenes for tumor therapy is the efficient delivery of siRNA into the cytosolic spaces of cancer cells. Here, we genetically bioengineer biomimetic nanovesicles with tumor-recognition and enzyme-controlled membrane fusion functions for efficiently delivering small interfering RNA into cancer cells towards gene silencing tumor therapy. The siRNA@eS-BNVs are formulated by encapsulating siRNA inside the core and coating with genetically engineered HEK293TACE2- cell membranes encoded with functional S protein, which can recognize cancer cells and initiate membrane fusion when triggered by the enzyme. The siRNA@eS-BNVs demonstrate better efficacy for cytosolic siRNA delivery and RNA interference than conventional formulations. By intravenous injection, siRNA@eS-BNVs are highly accumulated in tumors and potently inhibited tumor and lung metastasis by simultaneously silencing the epidermal growth factor receptor gene in vivo. The cancer cell-targeting and enzyme-activatable nanovesicles provide a valuable strategy for effective and precise drug delivery.

Date: 2025
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DOI: 10.1038/s41467-025-61230-1

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