Journal
JOURNAL OF EXTRACELLULAR VESICLES
Volume 11, Issue 3, Pages -Publisher
WILEY
DOI: 10.1002/jev2.12198
Keywords
tumour-derived extracellular vesicles; hybrid lipid nanovesicles; tumour homing; siRNA delivery; hepatocellular carcinoma
Categories
Funding
- National Natural Science Foundation of China [81973250, 82025032]
- Natural Science Foundation of Shanghai [21ZR1475800]
- State Key Laboratory of Drug Research [SIMM2103ZZ-01]
- Major International Joint Research Project of Chinese Academy of Sciences [153631KYSB20190020]
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This study successfully isolated TDEV membranes from hepatocellular carcinoma cells and fabricated innovative TDEV membrane hybrid lipid nanovesicles (LEVs) for precise delivery to tumors and efficient siRNA transfection. The LEVs, equipped with 'homing' targeting ability, showed improved siRNA delivery efficiency compared to liposomes. In animal experiments, siRNA loaded LEVs demonstrated enhanced antitumor efficacy in hepatocellular carcinoma tumors.
Extracellular vesicles (EVs) have been proved a promising small interfering RNA (siRNA) delivery vehicle to mediate gene-silencing. Tumour-derived extracellular vesicles (TDEVs) as genetic exchange vectors in the tumour microenvironment, enable intercellular communication for a wide range of endogenous cargo molecules, such as RNAs and proteins. However, the oncogenic cargo of TDEVs limits their application in siRNA delivery for cancer therapy. Herein, we isolated TDEVs from hepatocellular carcinoma (HCC) cells and derived TDEV membranes by abandoning their content. Innovative TDEV membrane hybrid lipid nanovesicles (LEVs) were then fabricated by fusion of TDEV membranes and phospholipids to realize precise delivery to tumours and highly efficient transfection of siRNA. The TDEV membranes endow LEVs with 'homing' targeting ability, facilitating specific internalisation into parent HCC cells primarily through heparan sulfate proteoglycan-mediated pathways. Unlike conventional lipid-based nanovesicles, LEVs can bypass the endosomal degradation pathway, boost the delivery of siRNA through the Golgi and endoplasmic reticulum (ER) intracellular 'freeway' transportation, achieving a 1.7-fold improvement in siRNA transfection efficiency compared with liposomes. Additionally, siRNA loaded LEVs were demonstrated to enhance the antitumour efficacy in HCC bearing mice through effective gene silencing in the tumour sites. Our results highlight the potential application of the TDEV membrane-derived nanovesicles as an advanced siRNA delivery strategy for cancer therapy.
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