γ-Amino Carboxylic Acid Modification Enhances the Efficacy of Peptide Nucleic Acids Targeting miR-221-3p in Lung Cancer Cell Lines

Peptide nucleic acids (PNAs) are versatile molecules with promising diagnostic and therapeutic applications, including gene expression regulation and miRNA targeting. However, their moderate biological efficacy limits their therapeutic application. This can be addressed by leveraging a key advantage of PNAs over other nucleic acids—the ease of modification, which enhances their functional properties. Notably, γ-modified PNAs have improved binding affinity and cellular uptake properties, underscoring the potential of backbone engineering. In this study, we introduced a novel γ-amino carboxylic acid modification into PNAs targeting miR-221-3p, a key miRNA implicated in various pathological processes. The binding affinity of the modified PNAs to their targets and their ability to inhibit miR-221-3p expression were considerably higher than those of unmodified PNAs in Lung cancer cell lines, leading to effective regulation of downstream gene and protein expression. These findings underscore the potential of γ-modified PNAs as a platform for developing miRNA-targeted therapeutics.