开发协同靶向疗法以提高治疗效果同时减少副作用已被证明是抗癌疗法的前景广阔，但如何方便地调节多药合作仍然是一个挑战。在此，提出了一种新颖的协同策略，使用包含 DNAzyme (DzG4) 和配体药物缀合物 (LDC) 两个亚基的 G-四联体编程多功能纳米机器人 (G4VN) 来精确靶向肿瘤，然后执行基因沉默和化疗。作为该纳米机器人的核心模块，精心设计的G4响应肿瘤微环境中的高水平K，巧妙地一石三鸟，使两个TfR适体贴近，提高其靶向肿瘤细胞的效率，并原位激活分裂的10-23 DNAzyme下调靶标mRNA表达，同时促进GSH反应性LDC的细胞摄取，从而增强药效。这种设计能够实现体内副作用低的有效协同抗癌疗法，在精准疾病治疗中显示出广泛应用的巨大前景。© 2024 Wiley‐VCH GmbH。

Developing synergistic targeted therapeutics to improve treatment efficacy while reducing side effects has proven promising for anticancer therapies, but how to conveniently modulate multidrug cooperation remains a challenge. Here, a novel synergistic strategy using a G-quadruplex-programmed versatile nanorobot (G4VN) containing two subunits of DNAzyme (DzG4) and ligand-drug conjugates (LDCs) is proposed to precisely target tumors and then execute both gene silencing and chemotherapy. As the core module of this nanorobot, a well-designed G4 responding to a high level of K+ in tumor microenvironment smartly kills three birds with one stone, which makes two TfR aptamers proximate to improve their efficiency of targeting tumor cells, and in situ activates a split 10-23 DNAzyme to downregulate target mRNA expression, meanwhile promotes the cell uptake of a GSH-responsive LDCs to enhance drug efficacy. Such a design enables a potently synergistic anticancer therapy with low side effects in vivo, showing great promise for broad applications in precision disease treatment.© 2024 Wiley‐VCH GmbH.