Intracellular delivery of proteins provides a direct means to manipulate cell function and probe the intracellular environment. However, direct cytoplasmic delivery of proteins suffers from limited availability of efficient toolsets, and thus remains challenging in research and therapeutic applications. Natural biological cargo delivery processes, like SNARE (soluble N-ethylmaleimide-sensitive factor attachment protein receptor) complex mediated membrane fusion and other vesicle fusion in live cells, enable targeted delivery with high efficiency. A surrogate of SNARE machinery represents a new direction in intracellular protein delivery. Here, we report a DNA-programmed membrane fusion strategy for guiding the efficient intracellular delivery of proteins into live cells. The inherent programmability of DNA hybridization provides spatiotemporal control of the fusion between protein-encapsulated liposomes and cell membranes, enabling rapid release of proteins directly into the cytoplasm, while still remaining functional due to the bypassing of the endosomal trap. We further demonstrate that delivered exogenous Cytochrome c effectively regulates the cell fate. Hence, this DNA-mediated fusion strategy holds great potential for protein drug delivery, regenerative medicine and gene editing.

中文翻译：

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使用DNA程序化膜融合技术指导蛋白质向活细胞中的递送†

蛋白质的细胞内递送提供了操纵细胞功能和探测细胞内环境的直接手段。然而，蛋白质的直接细胞质递送受到有效工具集的有限可用性的困扰，因此在研究和治疗应用中仍然具有挑战性。天然生物货物运输过程，例如SNARE（可溶性N-乙基马来酰亚胺敏感性因子附着蛋白受体）复合物介导的活细胞中的膜融合和其他囊泡融合，可实现高效靶向递送。SNARE机制的替代代表了细胞内蛋白质递送的新方向。在这里，我们报告了一种DNA编程的膜融合策略，用于指导将蛋白质有效地细胞内递送到活细胞中。DNA杂交的固有可编程性提供了时空控制蛋白封装脂质体和细胞膜之间融合的能力，从而使蛋白直接快速释放到细胞质中，同时由于绕过内体陷阱而仍保持功能。我们进一步证明，交付的外源细胞色素c有效调节细胞命运。因此，