Abstract: Exosomes or small extracellular vesicles are considered a new generation of bioinspired-nanoscale drug delivery system (DDS). Endogenous exosomes function as signalosomes since they convey signals via ligands or adhesion molecules located on the exosomal membrane, or packaged inside the exosome. Recently, exosome membrane modification, therapeutic payloads encapsulation, and modulation of in vivo disposition of exosomes have been extensively investigated, among which significant advances have been made to optimize exosome-mediated delivery to solid tumors. Exosomes, specifically tumor cell-derived exosomes, are presumed to have tumor-preferential delivery due to the homotypic features. However, quality attributes that dictate the tissue distribution, cell type-selective uptake, and intracellular payload release of the administered exosomes, as well as the spatiotemporal information regarding exosome fate in vivo, remain to be further investigated. This review summarizes recent advances in developing exosomes as drug delivery platforms with a focus on tumor targeting. The pharmacokinetic features of naive exosomes and factors influencing their intracellular fate are summarized. Recent strategies to improve tumor targeting of exosomes are also reviewed in the context of the biological features of tumor and tumor microenvironment (TME). Selected approaches to augment tumor tissue deposition of exosomes, as well as methods to enhance intracellular payload delivery, are summarized with emphasis on the underlying mechanisms (eg, passive or active targeting, endosomal escape, etc.). In conclusion, this review highlights recently reported tumor-targeting strategies of exosome-based drug delivery, and it’s in the hope that multiple approaches might be employed in a synergistic combination in the development of exosome-based cancer therapy.

Keywords: exosome, tumor-targeting, PK, drug delivery, nanovesicles


中文翻译：

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基于外泌体的药物递送和肿瘤靶向的进展：从组织分布到细胞内命运


摘要：外泌体或小细胞外囊泡被认为是新一代仿生纳米药物递送系统（DDS）。内源性外泌体起到信号体的作用，因为它们通过位于外泌体膜上或包装在外泌体内部的配体或粘附分子传递信号。最近，外泌体膜修饰、治疗有效负载封装和外泌体体内处置的调节已得到广泛研究，其中在优化外泌体介导的实体瘤递送方面取得了重大进展。由于同型特征，外泌体，特别是肿瘤细胞衍生的外泌体，被认为具有肿瘤优先递送能力。然而，决定外泌体的组织分布、细胞类型选择性摄取和细胞内有效负载释放的质量属性，以及有关外泌体体内命运的时空信息，仍有待进一步研究。本综述总结了开发外泌体作为药物递送平台的最新进展，重点是肿瘤靶向。总结了初始外泌体的药代动力学特征和影响其细胞内命运的因素。还结合肿瘤和肿瘤微环境（TME）的生物学特征回顾了最近改善外泌体肿瘤靶向的策略。总结了增强外泌体肿瘤组织沉积的选定方法，以及增强细胞内有效负载递送的方法，重点强调了潜在机制（例如，被动或主动靶向、内体逃逸等）。 总之，这篇综述重点介绍了最近报道的基于外泌体的药物递送的肿瘤靶向策略，并希望在基于外泌体的癌症治疗的开发中可以采用多种方法协同组合。


关键词:外泌体, 肿瘤靶向, PK, 药物递送, 纳米囊泡