Low oral bioavailability of peptide drugs has limited their application to parenteral administration, which suffers from poor patient compliance. Here, we show that molecular targeting of the FATP4 transporter is an effective approach to specifically transport long-chain fatty acid (LCFA)-conjugated peptides across the enterocytic membrane and, thus, enables oral delivery of drug peptides. We packaged LCFA-conjugated exendin-4 (LCFA-Ex4) into liposomes and coated with chitosan nanoparticles to form an orally deliverable Ex4 (OraEx4). OraEx4 protected LCFA-Ex4 from damage by the gastric fluid and released LCFA-Ex4 in the intestinal cavity, where LCFA-Ex4 was transported across the enterocyte membrane by the FAPT4 transporter. OraEx4 had a high bioavailability of 24.8% with respect to subcutaneous injection and exhibited a substantial hypoglycemic effect in murine models of diabetes mellitus. Thus, molecular targeting of the FATP4 transporter enhances oral absorption of therapeutic peptides and provides a platform for oral peptide drug development.

中文翻译：

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FATP4 转运蛋白的分子靶向用于治疗性肽的口服递送。

肽类药物的口服生物利用度较低，限制了其在肠外给药方面的应用，且患者依从性较差。在这里，我们证明 FATP4 转运蛋白的分子靶向是特异性转运长链脂肪酸 (LCFA) 缀合肽穿过肠细胞膜的有效方法，从而实现药物肽的口服递送。我们将 LCFA 缀合的 exendin-4 (LCFA-Ex4) 包装到脂质体中，并用壳聚糖纳米颗粒包被，形成可口服的 Ex4 (OraEx4)。OraEx4 保护 LCFA-Ex4 免受胃液损伤，并在肠腔中释放 LCFA-Ex4，其中 LCFA-Ex4 通过 FAPT4 转运蛋白跨肠细胞膜转运。OraEx4 皮下注射的生物利用度高达 24.8%，在糖尿病小鼠模型中表现出显着的降血糖作用。因此，FATP4转运蛋白的分子靶向增强了治疗性肽的口服吸收，并为口服肽药物开发提供了平台。