Rational Design of L‐RNA Aptamer‐Peptide Conjugate for Efficient Cell Uptake and G‐quadruplex‐Mediated Gene Control

RNA G-quadruplexes (D-rG4s) are prevalent in the transcriptome and play crucial regulatory roles in various biological processes. Recently, L-RNA aptamers have been reported to recognize functional rG4s with a strong binding affinity and specificity. However, owing to the poor cell penetration capacity of L-RNA aptamers, their biological applications are currently limited. Herein, we rationally design an L-RNA aptamer-peptide conjugate, Tamra_Ahx_R8_L-Apt.4-1c, which can efficiently translocate into the cytosol and target the rG4 of interest. Notably, we demonstrate diverse regulatory roles of Tamra_Ahx_R8_L-Apt.4-1c on rG4 motif present in different regions of mRNAs and further expand the application in different cell lines. Our novel and biocompatible conjugate enhances the cellular uptake of the L-RNA aptamer, and our robust strategy enables non-canonical RNA structures to be targeted by L-RNA aptamers for gene control in cells.