Efficient cytosolic delivery is a significant hurdle when using short interfering RNA (siRNA) in therapeutic applications. Here we show that cholesterol-rich exosomes are prone to entering cancer cells through membrane fusion, achieving direct cytosolic delivery of siRNA. Molecular dynamics simulations suggest that deformation and increased contact with the target cell membrane facilitate membrane fusion. In vitro we show that cholesterol-enriched milk-derived exosomes (MEs) achieve a significantly higher gene silencing effect of siRNA, inducing superior cancer cell apoptosis compared with the native and cholesterol-depleted MEs, as well as conventional transfection agents. When administered orally or intravenously to mice bearing orthotopic or subcutaneous tumours, the cholesterol-enriched MEs/siRNA exhibit antitumour activity superior to that of lipid nanoparticles. Collectively, by modulating the cholesterol content of exosome membranes to facilitate cell entry via membrane fusion, we provide a promising approach for siRNA-based gene therapy, paving the way for effective, safe and simple gene therapy strategies.

Yan Zhuo

Zhen Luo

Zhu Zhu

Jie Wang

Xiang Li

Zhuan Zhang

Cong Guo

Bingqi Wang

Di Nie

Yong Gan

Guoqing Hu

Miaorong Yu

Nature Nanotechnology

NATURE NANOTECHNOLOGY 是一本跨学科期刊，在纳米科学和纳米技术的所有领域发表最高质量和最重要的论文。该杂志涵盖了对结构、设备和系统的设计、表征和生产的研究，这些研究涉及在原子、分子和大分子尺度上对材料和现象的操纵和控制。涵盖了自下而上和自上而下的方法——以及两者的结合。自然纳米技术还鼓励化学家、物理学家、材料科学家、生物医学研究人员、工程师和其他活跃在该领域前沿的研究人员之间的思想交流多元化和多学科领域。覆盖范围从物理、化学和生物学的基础研究，包括计算工作和模拟，到新设备和技术的开发，以应用于广泛的工业领域（包括信息技术、医学、制造、高性能材料、以及能源和环境技术）。有机、无机和杂化材料一应俱全。期刊涵盖的研究领域：-碳纳米管和富勒烯-计算纳米技术-电子特性和器件-环境、健康和安全问题-分子机器和电机-分子自组装-纳米生物技术-纳米流体-纳米磁性和自旋电子学-纳米材料-纳米医学-纳米计量和仪器-纳米粒子-纳米传感器和其他器件-NEMS-有机-无机纳米结构-光子结构和器件-量子信息-结构特性-表面图案化和成像-合成和加工

NATURE NANOTECHNOLOGY is an interdisciplinary journal that publishes high-quality and significant papers in all areas of nanoscience and nanotechnology. The journal covers research on the design, characterization, and production of structures, devices, and systems that manipulate and control materials and phenomena at the atomic, molecular, and macromolecular scales. It encompasses both bottom-up and top-down approaches, as well as combinations of the two. NATURE NANOTECHNOLOGY encourages the exchange of ideas among chemists, physicists, materials scientists, biomedical researchers, engineers, and other researchers active at the forefront of the field, fostering diversity and interdisciplinary collaboration. The scope includes fundamental research in physics, chemistry, and biology, computational work and simulations, as well as the development of new devices and technologies for applications across a wide range of industrial sectors, including information technology, medicine, manufacturing, high-performance materials, and energy and environmental technologies. The journal covers research areas such as: carbon nanotubes and fullerenes, computational nanotechnology, electronic properties and devices, environmental, health, and safety issues, molecular machines and motors, molecular self-assembly, nanobiotechnology, nanofluids, nanomagnetism and spintronics, nanomaterials, nanomedicine, nanometrology and instrumentation, nanoparticles, nanosensors and other devices, NEMS, organic-inorganic nanostructures, photonic structures and devices, quantum information, structural properties, surface patterning and imaging, synthesis and processing.

NATURE NANOTECHNOLOGY 是一本跨学科期刊，发表纳米科学和纳米技术领域的高质量和重要论文。该杂志研究材料和现象在原子、分子和大分子尺度上的操控与控制，涵盖结构、设备和系统的设计、表征和生产。期刊涉及自下而上和自上而下的方法，以及两者的结合。NATURE NANOTECHNOLOGY 鼓励化学家、物理学家、材料科学家、生物医学研究人员、工程师及其他领域的研究人员之间的思想交流，促进多元化和跨学科的合作。覆盖范围包括物理、化学和生物学的基础研究，计算工作和模拟，以及新设备和技术的开发，应用于信息技术、医学、制造、高性能材料、能源和环境技术等多个工业领域。期刊涵盖的研究领域包括：碳纳米管和富勒烯、计算纳米技术、电子特性和器件、环境、健康和安全问题、分子机器和电机、分子自组装、纳米生物技术、纳米流体、纳米磁性和自旋电子学、纳米材料、纳米医学、纳米计量和仪器、纳米粒子、纳米传感器和其他器件、NEMS、有机-无机纳米结构、光子结构和器件、量子信息、结构特性、表面图案化和成像、合成和加工。

Nat. Nanotechnol.

Direct cytosolic delivery of siRNA via cell membrane fusion using cholesterol-enriched exosomes

通过胆固醇富集的外泌体实现细胞膜融合介导的siRNA直接细胞质递送

Category	Quartile
材料科学	1
材料科学, 材料科学综合	1
材料科学, 纳米科技	1

Direct cytosolic delivery of siRNA via cell membrane fusion using cholesterol-enriched exosomes

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