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

ABSTRACT 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.