Currently, small extracellular vesicles (sEV) as a nanoscale drug delivery system, are undergoing biotechnological scaling and clinical validation. Nonetheless, preclinical pharmacokinetic studies revealed that sEV are predominantly uptaken by macrophages. Although this “sEV-macrophage” propensity represents a disadvantage in terms of sEV targeting and their bioavailability as nanocarriers, it also represents a strategic advantage for those therapies that involve macrophages. Such is the case of tumor-associated macrophages (TAMs), which can reprogram/repolarize their predominantly immunosuppressive and tumor-supportive phenotype toward an immunostimulatory and anti-tumor phenotype using sEV as nanocarriers of TAMs reprogramming molecules. In this design, sEV represents an advantageous delivery system, providing precision to the therapy by simultaneously matching their tropism to the therapeutic cell target. Here, we review the current knowledge of the role of TAMs in the tumoral microenvironment and the effect generated by the reprogramming of these phagocytic cells fate using sEV. Finally, we discuss how these vesicles can be engineered by different bioengineering techniques to improve their therapeutic cargo loading and preferential uptake by TAMs.

中文翻译：

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化逆境为机遇：小细胞外囊泡作为肿瘤相关巨噬细胞再教育的纳米载体

目前，小细胞外囊泡（sEV）作为纳米级药物递送系统，正在进行生物技术缩放和临床验证。尽管如此，临床前药代动力学研究表明，sEV 主要被巨噬细胞摄取。尽管这种“sEV-巨噬细胞”倾向代表了 sEV 靶向及其作为纳米载体的生物利用度方面的劣势，但它也代表了那些涉及巨噬细胞的疗法的战略优势。肿瘤相关巨噬细胞 (TAM) 就是这种情况，它可以使用 sEV 作为 TAM 重编程分子的纳米载体，将其主要的免疫抑制和肿瘤支持表型重新编程/重新极化为免疫刺激和抗肿瘤表型。在这个设计中，sEV 代表了一个有利的传递系统，通过同时将它们的趋向性与治疗细胞靶标相匹配来提供精确的治疗。在这里，我们回顾了目前关于 TAM 在肿瘤微环境中的作用的知识，以及使用 sEV 重编程这些吞噬细胞命运所产生的影响。最后，我们讨论了如何通过不同的生物工程技术对这些囊泡进行工程改造，以改善它们的治疗性货物装载和 TAM 的优先摄取。