位点特异性化学共轭一直是在配体定向修饰领域中一个具有挑战性的工作，以生产用于精准医学的均一共轭物。在这里，我们开发了一种化学放大启动的拓扑修饰（Chem-ATM）方法，为核酸适配体的可编程修饰与指定功能建立了一个多用途平台。与常规的共轭策略不同，Chem-ATM设计了一个三维人工碱基作为化学放大器，使得适配体具有结构和功能多样性的共轭成为可能，同时能够精确控制负载能力，但与序列无关。与此同时，sp3杂化原子含有的放大器使得整个共轭物在复杂的生物环境中发生平面到立体的构象转变，从而引起高度的立体位阻，对酶降解具有很高的抵抗能力。Chem-ATM的多功能性已通过其输送抗癌药物和成像剂在裸鼠异种移植肿瘤和正位移植肿瘤模型中成功展示出来，以实现增强疗法和高对比度的非侵入性肿瘤成像。本研究为配体定向化学共轭提供了一个不同的视角，丰富了生物成像和药物开发的分子工具箱。

Site-specific chemical conjugation has long been a challenging endeavor in the field of ligand-directed modification to produce homogeneous conjugates for precision medicine. Here, we develop a chemical amplification-enabled topological modification (Chem-ATM) methodology to establish a versatile platform for the programmable modification of nucleic acid aptamers with designated functionalities. Differing from conventional conjugation strategies, a three-dimensional artificial base is designed in Chem-ATM as a chemical amplifier, giving access to structurally and functionally diversified conjugation of aptamers, with precise control over loading capacity but in a sequence-independent manner. Meanwhile, the sp3 hybridized atom-containing amplifier enables planar-to-stereo conformational transformation of the entire conjugate, eliciting high steric hindrance against enzymatic degradation in complex biological environments. The versatility of Chem-ATM is successfully demonstrated by its delivery of anticancer drugs and imaging agents for enhanced therapy and high-contrast noninvasive tumor imaging in xenograft and orthotopic tumor models. This study offers a different perspective for ligand-directed chemical conjugation to enrich the molecular toolbox for bioimaging and drug development.