Next-generation nanocarriers for therapeutic oligonucleotides: Precision targeting and stimuli-responsive cancer...

Therapeutic oligonucleotides (TOs) have emerged as a promising gene therapy approach for tumor treatment, offering high specificity and therapeutic efficacy by directly modulating target gene expression and subsequent protein synthesis. However, the clinical translation of TOs remains hindered by critical challenges, including suboptimal targeting efficiency, insufficient responsiveness, lysosomal entrapment, poor stability, and potential off-target effects. To address these limitations, advanced delivery systems with precise targeting and stimuli-responsive capabilities are essential. Nanocarrier systems, characterized by their high targeting precision and controlled drug release, have gained widespread application in tumor gene therapy. Integrating TOs with intelligent nanocarrier systems enables safe, stable, efficient, and targeted delivery to tumor tissues, presenting a highly promising strategy for precise cancer gene therapy. This review provides a comprehensive overview of current advancements in the design of intelligent nanoparticles for TOs delivery. It discusses the classification of TOs and their therapeutic mechanisms, the categorization of nanocarriers, the binding modes between TOs and nanomaterials, and strategies to achieve tumor-specific targeting and responsiveness. By addressing these critical design considerations, this review aims to inform the development of next-generation nanomaterials for improved TOs-based tumor therapy.