2. Academic Validation
  3. Bioswitchable intracellular delivery of small activating RNA by tetrahedral framework nucleic acid: Application to p21-mediated anti-tumor therapy

Bioswitchable intracellular delivery of small activating RNA by tetrahedral framework nucleic acid: Application to p21-mediated anti-tumor therapy

  • J Control Release. 2026 Jan 10:389:114488. doi: 10.1016/j.jconrel.2025.114488.
Yuhao Liu 1,  Shiyu Lin 2,  Lulu Liang 3,  Zhengwen Cai 4,  Weijie Zhuang 5,  Xiangyi Chen 5,  Lechuan Gao 6,  Songhang Li 4,  Yunfeng Lin 7
Affiliations

Affiliations

  • 1 School of Stomatology, Binzhou Medical University, Yantai 264003, China; Hospital of Stomatology, Guanghua School of Stomatology, Guangdong Provincial Key Laboratory of Stomatology, Sun Yat-sen University, Guangzhou 510055, China.
  • 2 Department of Oral Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, College of Stomatology, Shanghai Jiao Tong University, Shanghai 200011, China.
  • 3 Guangzhou Development District Hospital, Chinese Association of Medicinal Biotechnology, Southern Center of Biology Diagnosis and Therapy, Guangzhou 510730, China.
  • 4 State Key Laboratory of Oral Diseases, National Center for Stomatology, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China.
  • 5 Hospital of Stomatology, Guanghua School of Stomatology, Guangdong Provincial Key Laboratory of Stomatology, Sun Yat-sen University, Guangzhou 510055, China.
  • 6 School of Stomatology, Binzhou Medical University, Yantai 264003, China.
  • 7 State Key Laboratory of Oral Diseases, National Center for Stomatology, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China; Sichuan Provincial Engineering Research Center of Oral Biomaterials, Chengdu, Sichuan 610041, China. Electronic address: [email protected].
PMID: 41330514 DOI: 10.1016/j.jconrel.2025.114488
Abstract

Small activating RNA (saR) has garnered increasing attention in the biomedical field due to its unique RNA activation function. However, as a short-sequence, double-stranded oligonucleotide, saR's efficacy heavily relies on the delivery efficiency of the vehicle, as well as the accuracy and reliability of saR loading and dissociation. The tetrahedral framework nucleic acid has been established as an effective carrier for oligonucleotides, but its application in saR delivery remains limited. In this study, p21-saR, which upregulates the p21 gene to induce cellular senescence, was selected as a model saR. p21-saR was loaded onto the tetrahedral framework nucleic acid (t-saR) via DNA/RNA hybrid sticky ends. Upon efficient uptake by SCC-9 cells, t-saR underwent sticky end shearing triggered by intracellular RNase H, resulting in the dynamic release of saR and the screening of its guide strand. Through targeted activation of the p21/Rb signaling pathway, t-saR promoted senescence in SCC-9 cells and inhibited tumor growth in vivo, demonstrating superior therapeutic efficacy compared to the saR monomer. In conclusion, the bioswitchable t-saR effectively achieves RNA activation and holds significant promise for biomedical applications.

Keywords

Anti-tumor therapy; Small activating RNA; Tetrahedral framework nucleic acid; p21.

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