Direct transmembrane transport plays an important role in the biomedical field. Although well-established methods exist for the direct membrane transport of small-sized cargoes (e.g., water and ions) and large-sized cargoes (e.g., proteins, DNAs, polysaccharides), they are challenging to directly apply to medium-sized cargoes (e.g., drugs, probes, oligopeptides, and growth hormones). Here, we present a negatively charged single molecular carrier, carboxyl-modified azocalix[6]arene (CAC6A), as a direct transmembrane tool that facilitates the transport of medium-sized cargoes. The cellular uptake pathway of CAC6A was identified using pharmacological inhibitors, and the direct transmembrane transport was confirmed. Further mechanistic transport investigations reveal that the modification group at the upper rim, the cavity size, and the appropriate amphiphilicity of CAC6A promote direct membrane transport. Combined with the hypoxia-responsive property, CAC6A achieved the targeted release of the payload. The findings in this work may lead to the development of macrocycle-based transmembrane systems with broad applications in biomedicine, diagnostics, and sensing.

中文翻译：

---

单分子大环载体克服了中型货物的直接跨膜

直接跨膜转运在生物医学领域发挥着重要作用。尽管存在小型货物（例如水和离子）和大型货物（例如蛋白质、DNA、多糖）的直接膜运输的成熟方法，但它们直接应用于中型货物（例如药物、探针、寡肽和生长激素）具有挑战性。在这里，我们提出了一种带负电荷的单分子载体，羧基修饰的偶氮卡利[6]芳烃 （CAC6A），作为一种直接跨膜工具，有助于中型货物的运输。使用药理学抑制剂鉴定 CAC6A 的细胞摄取途径，并确认直接跨膜转运。进一步的机制运输研究表明，上缘的修饰基团、腔体大小和 CAC6A 的适当两亲性促进了直接膜转运。结合缺氧响应特性，CAC6A 实现了有效载荷的靶向释放。这项工作的发现可能会导致基于大周期的跨膜系统的发展，该系统在生物医学、诊断和传感方面具有广泛的应用。