Automated attachment of chemotherapeutic drugs to oligonucleotides through phosphoramidite chemistry and DNA synthesis has emerged as a powerful technology in constructing structure‐defined and payload‐tunable oligonucleotide–drug conjugates. In practice, however, in vivo delivery of these oligonucleotides remains a challenge. Inspired by the systemic transport of hydrophobic payloads by serum albumin in nature, we report the development of a lipid‐conjugated floxuridine homomeric oligonucleotide (LFU20) that “hitchhikes” with endogenous serum albumin for cancer chemotherapy. Upon intravenous injection, LFU20 immediately inserts into the hydrophobic cave of albumin to form an LFU20/albumin complex, which accumulates in the tumor by the enhanced permeability and retention (EPR) effect and internalizes into the lysosomes of cancer cells. After degradation, cytotoxic floxuridine monophosphate is released to inhibit cell proliferation.

中文翻译：

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氟尿苷同聚寡核苷酸“ Hitchhike”与白蛋白原位用于癌症化学治疗

通过亚磷酰胺化学反应和DNA合成将化学治疗药物自动连接至寡核苷酸已成为构建结构定义和有效负载可调的寡核苷酸-药物偶联物的强大技术。然而，实际上，这些寡核苷酸的体内递送仍然是挑战。受自然界中血清白蛋白对疏水性有效负载的系统性运输的启发，我们报告了脂质缀合的氟尿苷同聚寡核苷酸（LFU20）的开发，该寡核苷酸与内源性血清白蛋白“搭便车”用于癌症化疗。静脉注射后，LFU20立即插入白蛋白的疏水洞中，形成LFU20 /白蛋白复合物，该复合物通过增强的通透性和保留（EPR）效应积聚在肿瘤中，并内化到癌细胞的溶酶体中。