Department of Pharmacology Yong Loo Lin School of Medicine National University of Singapore Singapore.
Department of Biomedical Sciences College of Veterinary Medicine and Life Sciences City University of Hong Kong Hong Kong.
J Extracell Vesicles. 2021 Feb;10(4):e12057. doi: 10.1002/jev2.12057. Epub 2021 Feb 16.
Natural extracellular vesicles (EVs) are ideal drug carriers due to their remarkable biocompatibility. Their delivery specificity can be achieved by the conjugation of targeting ligands. However, existing methods to engineer target-specific EVs are tedious or inefficient, having to compromise between harsh chemical treatments and transient interactions. Here, we describe a novel method for the covalent conjugation of EVs with high copy numbers of targeting moieties using protein ligases. Conjugation of EVs with either an epidermal growth factor receptor (EGFR)-targeting peptide or anti-EGFR nanobody facilitates their accumulation in EGFR-positive cancer cells, both and . Systemic delivery of paclitaxel by EGFR-targeting EVs at a low dose significantly increases drug efficacy in a xenografted mouse model of EGFR-positive lung cancer. The method is also applicable to the conjugation of EVs with peptides and nanobodies targeting other receptors, such as HER2 and SIRP alpha, and the conjugated EVs can deliver RNA in addition to small molecules, supporting the versatile application of EVs in cancer therapies. This simple, yet efficient and versatile method for the stable surface modification of EVs bypasses the need for genetic and chemical modifications, thus facilitating safe and specific delivery of therapeutic payloads to target cells.
天然细胞外囊泡（EVs）具有显著的生物相容性，是理想的药物载体。通过连接靶向配体，可以实现其递药的特异性。然而，现有的工程化靶向 EVs 的方法繁琐或效率低下，必须在苛刻的化学处理和瞬时相互作用之间做出妥协。在这里，我们描述了一种使用蛋白连接酶将 EVs 与高拷贝数的靶向部分进行共价连接的新方法。EVs 与表皮生长因子受体（EGFR）靶向肽或抗 EGFR 纳米体的连接促进了它们在 EGFR 阳性癌细胞中的积累，无论是在 细胞内还是在 细胞外。用 EGFR 靶向 EVs 以低剂量递送紫杉醇可显著提高 EGFR 阳性肺癌异种移植小鼠模型中的药物疗效。该方法还适用于将 EVs 与针对其他受体（如 HER2 和 SIRPα）的肽和纳米体进行偶联，并且偶联的 EVs 除了小分子之外还可以递送 RNA，支持 EVs 在癌症治疗中的多功能应用。这种简单、高效且多功能的 EVs 表面稳定修饰方法绕过了对遗传和化学修饰的需求，从而促进了治疗有效载荷向靶细胞的安全和特异性递送。
