Nucleic Acid Therapeutics for “Undruggable” Cancer Targets: Mechanisms, Challenges, and Prospects

ABSTRACT Despite significant advances in precision oncology, key oncoproteins such as Ras, MYC, and p53 remain historically difficult to drug. Conventional pharmacologic strategies are fundamentally constrained by their dependency on direct interactions with well‐defined structural domains, which these targets lack. Nucleic acid therapeutics offer a transformative paradigm to overcome this central limitation by redirecting pharmacological intervention to the mRNA and genomic levels, thereby operating independently of complex protein structures. In this review, we systematically examine the mechanisms of action and translational progress of diverse nucleic acid modalities, including ASOs, siRNAs, miRNAs, aptamers, and mRNA vaccines against these intractable targets. We comprehensively discuss their mechanisms, such as transcript degradation, translational inhibition, and upstream regulatory interference. Furthermore, we critically analyze the primary translational bottlenecks, specifically focusing on delivery efficiency, safety profiling, and scalable manufacturing, while highlighting recent advances in nanocarrier platforms. Finally, we explore future directions enabled by emerging technologies and computational design. Ultimately, this review highlights how nucleic acid therapeutics represent a paradigm shift, enabling precise regulation of “undruggable” cancer targets.