Cancer remains one of the leading causes of mortality worldwide (Wu et al., 2024). Traditional treatments such as radiotherapy and chemotherapy often result in severe side effects, which seriously affect patient outcomes (Ahmad et al., 2012). Therefore, there is an urgent need for a safe, effective, and precisely controllable therapeutic approach to overcome the clinical challenges in cancer treatment.

RNA interference (RNAi) is considered a highly specific gene-silencing strategy that minimizes off-target effects on normal cells compared to conventional radiotherapy and chemotherapy, demonstrating great potential in cancer treatment(Schaue & McBride, 2015; Trone et al., 2017). This class of gene therapy–based therapeutic RNAs, known as therapeutic oligonucleotides (TOs), represents a precise gene-silencing method, which can be harnessed to specifically target cancer cells and reduce the adverse effects of conventional therapies on normal tissues. This strategy holds significant promise for improving cancer treatment outcomes (Chang et al., 2021; Chen et al., 2018). To date, 17 TOs-based drugs have been approved by the FDA, including six small interfering RNAs (siRNAs) and 11 antisense oligonucleotides. Furthermore, numerous other TOs formulations are currently undergoing clinical trials, including those targeting Endogenous Retrovirus-9 Long Terminal Repeat, B-cell lymphoma 2, and telomerase (GRN163) (Wang et al., 2020).

Despite the great potential of TOs in cancer treatment, their clinical application is hindered by several challenges, such as rapid clearance, short half-life, poor membrane penetration, and insufficient targeting capability. Additionally, even when TOs are successfully internalized by target cells, only a small fraction is able to escape from the endosome and enter the cytoplasm to exert their therapeutic effects. To overcome these limitations, the development of advanced delivery systems is crucial. Nanomaterials have emerged as promising carriers for TOs delivery due to their unique properties, including diverse structural forms, modifiability, and inherent therapeutic potential. Nanomaterials can be engineered to enhance the stability, bioavailability, and targeted delivery of TOs while reducing systemic side effects. By modifying their biochemical composition, charge, size, and surface functional groups, nanomaterials can be tailored to respond to the specific conditions of the tumor microenvironment, thus improving the therapeutic efficacy of TOs. This approach enables not only the stabilization of TOs and the extension of their half-life but also the development of intelligent nanomaterials capable of targeted delivery and responsive release within the tumor site. By enhancing the bioavailability of TOs and minimizing systemic side effects, these systems represent a promising strategy for improving the therapeutic efficiency of TO-based therapies.

Despite the significant progress in this area, there is currently a lack of comprehensive reviews that systematically evaluate the design strategies of intelligent nanomaterials for targeted and responsive delivery of TOs. Given the effectiveness and innovation of responsive nanocarrier systems for TOs in cancer treatment, this review aims to provide insights into design strategies and potential research directions for intelligent nanoparticles (Fig.1). It will elaborate on the classification and mechanisms of therapeutic RNA in cancer treatment, highlighting the limitations of monomeric RNA. Based on this foundation, the review will propose innovative design principles for nanocarrier systems, focusing on strategies for targeted delivery through biochemical modifications and responsive release triggered by tumor-specific factors. Ultimately, this review aims to facilitate the development of TO-based nanomedicines with improved safety, enhanced efficiency, and greater precision for cancer therapy.