AND‐Logic‐Gated Aptamer Switch for Precise Targeting and Regulation of RNA G‐Quadruplexes

RNA G-quadruplexes (rG4s) play critical roles in gene regulation and cancer progression, yet their precise manipulation in tumor cells remains challenging. rG4-targeting L-RNA aptamers are an emerging class of ligands with exceptional affinity for rG4s; however, their lack of cell type-specific delivery hinders their regulatory and therapeutic potential. Herein, we engineer an activatable bispecific aptamer switch, termed the Allosteric RNA G-quadruplex ON-switch (ARGON), which integrates an rG4-targeting L-RNA Apt.4-1c module (masked by a glutathione (GSH)-cleavable lock strand) with a tumor receptor-targeting Sgc8 DNA aptamer to precisely target rG4s and regulate downstream cellular activities within tumor cells. The AND logic-gated ARGON is activated exclusively in tumor cells that exhibit both tumor receptor overexpression and elevated GSH levels. Following cellular uptake, GSH-triggered lock cleavage exposes L-Apt.4-1c's rG4-binding domain, enabling binding oncogenic Bcl2 rG4. Then activated ARGON regulates rG4-associated tumor cellular functions while sparing normal cells. Besides, we apply ARGON to target human telomerase RNA component (hTERC) rG4 to show our method's generality. Collectively, by integrating cell-surface addressing with intracellular environmental sensing, our work reports an "old-chemistry-new-trick" framework for regulating nucleic acid structures, enabling conditional targeting of cellular RNA structures with minimal off-target effects and propelling aptamer-based precision biomedicine forward.