G‐Quadruplex‐Programmed Versatile Nanorobot Combined with Chemotherapy and Gene Therapy for Synergistic Targeted Therapy

Abstract 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.