Rationale: Developing an effective nanoplatform to realize 'multi-in-one' is essential to broaden the therapeutic potential of combination therapy. Exosomes are ideal candidates since their intrinsic abilities of integrating multiple contents and functions. However, only limited efforts have been devoted to engineering exosomes to integrate the needed properties, also considering the safety and yield, for tumor-targeted and efficient gene/chemo combination therapy./nMethods: Herein, by manipulating the exosome membrane, blood exosomes with high abundance and safety are engineered as a versatile combinatorial delivery system, where the doxorubicin (Dox) and cholesterol-modified miRNA21 inhibitor (miR-21i) are co-embedded into the lipid bilayer of exosomes, and the magnetic molecules and endosomolytic peptides L17E are bind to the exosome membrane through ligand-receptor coupling and electrostatic interactions, respectively./nResults: It is proved that such engineering strategy not only preserves their intrinsic features, but also readily integrates multiple properties of tumor targeting, efficient transfection and gene/chemo combination therapy into blood exosomes. The lipid bilayer structure of exosomes allows them to co-load Dox and miR-21i with high-payloads. Moreover, profiting from the integration of magnetic molecules and L17E peptides, the engineered exosomes exhibit an enhanced tumor accumulation and an improved endosome escape ability, thereby specifically and efficiently delivering encapsulated cargos to tumor cells. As a result, a remarkable inhibition of tumor growth is observed in the tumor-bearing mice, and without noticeable side effects./nConclusions: This study demonstrates the potential of engineered blood exosomes as feasible co-delivery nanosystem for tumor-targeted and efficient combination therapy. Further development by replacing the drugs combined regimens can potentially make this engineered exosome become a general platform for the design of safe and effective combination therapy modality.

中文翻译：

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工程血液外泌体，用于靶向肿瘤的有效基因/化学联合疗法。

原理：开发有效的纳米平台以实现“多合一”对扩大联合疗法的治疗潜力至关重要。外来体是理想的候选者，因为它们具有整合多种内容和功能的内在能力。然而，只有有限的努力，一直致力于工程的外来体整合所需的性能，还要考虑安全性和收益率，为肿瘤靶向，高效的基因/化疗组合therapy./n方法：在此，通过操纵外泌体膜，将具有高丰度和安全性的血液外泌体设计为通用的组合递送系统，其中将阿霉素（Dox）和胆固醇修饰的miRNA21抑制剂（miR-21i）共嵌入脂质体的脂质双层中外来体，和磁性分子和核内体溶解肽L17E被结合到通过配体-受体偶联和静电相互作用，respectively./n外来体膜结果：事实证明，这种工程策略不仅保留了其固有特征，而且还易于将肿瘤靶向，有效转染和基因/化学联合疗法的多种特性整合到血液外泌体中。外泌体的脂质双层结构使它们可以高负载同时负载Dox和miR-21i。此外，得益于磁性分子和L17E肽的整合，工程化的外泌体显示出增强的肿瘤积累和改善的内体逃逸能力，从而特异且有效地将封装的货物递送至肿瘤细胞。结果，在荷瘤小鼠中观察到了显着的肿瘤生长抑制作用，并且没有明显的副作用。/n结论：这项研究证明了工程化血液外泌体作为肿瘤靶向和有效联合治疗可行的共输送纳米系统的潜力。通过替代药物联合疗法的进一步开发可能使这种工程化的外泌体成为设计安全有效联合疗法的通用平台。