Nanomedicines often rely on noncovalent self-assembly and encapsulation for drug loading and delivery. However, challenges such as reproducibility issues due to the multicomponent nature, off-target activation caused by premature drug release, and complex pharmacokinetics arising from assembly dissociation have hindered their clinical translation. In this study, we introduce an innovative design concept termed single molecular nanomedicine (SMNM) based on macrocyclic carrier-drug conjugates. Through the covalent linkage of two chemotherapy drugs to a hypoxia-cleavable macrocyclic carrier, azocalix[4]arene, we obtained two self-included complexes to serve as SMNMs. The intramolecular inclusion feature of the SMNMs has not only demonstrated comprehensive shielding and protection for the drugs but also effectively prevented off-target drug leakage, thereby significantly reducing their side effects and enhancing their antitumor therapeutic efficacy. Additionally, the attributes of being a single component and molecularly dispersed confer advantages such as ease of preparation and good reproducibility for SMNMs, which is desirable for clinical applications.

中文翻译：

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基于大环载体-药物缀合物的单分子纳米药物，用于浓度无关的封装和药物的精确激活


纳米药物通常依赖于非共价自组装和封装来进行药物装载和递送。然而，由于多组分性质导致的重现性问题、药物过早释放引起的脱靶激活以及组装解离引起的复杂药代动力学等挑战阻碍了其临床转化。在这项研究中，我们引入了一种基于大环载体-药物缀合物的创新设计概念，称为单分子纳米药物（SMNM）。通过将两种化疗药物与缺氧可裂解的大环载体 azocalix[4] 芳烃共价连接，我们获得了两种自包含复合物作为 SMNM。 SMNMs的分子内包合特性不仅对药物具有全面的屏蔽和保护作用，还能有效防止药物脱靶渗漏，从而显着降低其副作用，增强其抗肿瘤治疗效果。此外，单一成分和分子分散的特性赋予了 SMNM 易于制备和良好重现性等优点，这对于临床应用来说是理想的。