Vol. 1 No. 1 (2025)

Articles

pH-Responsive Mesoporous Silica Nanoparticles Functionalized with Aptamers for Targeted siRNA Delivery in Triple-Negative Breast Cancer Therapy

Published 2025-07-30

  • Emily S. Wong

Emily S. Wong
Department of Oncology, Massachusetts General Hospital, Boston, MA 02114, USA

Abstract

Triple-negative breast cancer (TNBC) remains a recalcitrant malignancy due to its lack of hormone receptors and HER2 overexpression, limiting targeted therapy options. Small interfering RNA (siRNA)-based therapy holds promise for TNBC by silencing oncogenes, but its clinical translation is hindered by poor stability, low cellular uptake, and off-target effects. Herein, we developed a pH-responsive mesoporous silica nanoparticle (MSN) system functionalized with AS1411 aptamers for targeted siRNA delivery to TNBC cells. The MSNs were engineered with a pH-sensitive poly(β-amino ester) (PBAE) coating to facilitate endosomal escape and surface-conjugated with AS1411, which binds to nucleolin overexpressed on TNBC cell membranes. The siRNA targeting MCL-1 (a prosurvival oncogene) was loaded into the MSN pores via electrostatic interaction. In vitro studies showed that the aptamer-functionalized MSNs (Apt-MSNs) exhibited 3.2-fold higher cellular uptake in MDA-MB-231 TNBC cells than non-targeted MSNs, leading to 82.3% MCL-1 silencing and 67.5% cell apoptosis. In vivo, Apt-MSN/siMCL-1 significantly inhibited tumor growth in TNBC xenograft mice (tumor volume reduction of 71.2% vs. saline control) and reduced systemic toxicity, as evidenced by normal liver/kidney function and minimal organ damage. This work demonstrates the potential of aptamer-functionalized, pH-responsive MSNs as a targeted nanoplatform for siRNA delivery in TNBC therapy, highlighting the convergence of nanomaterial engineering and biomedicine for precision cancer treatment.

Keywords

Mesoporous Silica Nanoparticles; Aptamer Targeting; pH-Responsive Delivery; siRNA; Triple-Negative Breast Cancer; Nanomedicine; Oncogene Silencing; Drug Delivery Systems

PDF

References

  1. [1] Siegel, R. L., Miller, K. D., & Jemal, A. (2023). Cancer statistics, 2023. CA: A Cancer Journal for Clinicians, 73(1), 17–48.
  2. [2] Foulkes, W. D., Smith, I. E., & Reis-Filho, J. S. (2010). Triple-negative breast cancer. The New England Journal of Medicine, 363(20), 1938–1948.
  3. [3] Chen, Y., Zhang, L., & Liu, X. (2022). siRNA-based therapy for triple-negative breast cancer: Challenges and opportunities. Journal of Controlled Release, 345, 668–685.
  4. [4] Fire, A., Xu, S., Montgomery, M. K., et al. (1998). Potent and specific genetic interference by double-stranded RNA in Caenorhabditis elegans. Nature, 391(6669), 806–811.
  5. [5] Davis, M. E., Zuckerman, J. E., Choi, C. H., et al. (2010). Evidence of RNAi in humans from systemically administered siRNA via targeted nanoparticles. Nature, 464(7291), 1067–1070.
  6. [6] Vallet-Regí, M., Rámila, A., del Real, R. P., et al. (2001). A new property of MCM-41: Drug delivery system. Chemistry of Materials, 13(10), 308–311.
  7. [7] Slowing, I. I., Vivero-Escoto, J. L., Trewyn, B. G., et al. (2008). Mesoporous silica nanoparticles for controlled release drug delivery. Advanced Drug Delivery Reviews, 60(11), 1278–1288.
  8. [8] Wang, Y., Li, J., & Zhang, Q. (2021). Mesoporous silica nanoparticles: Synthesis, surface functionalization, and biomedical applications. Chemical Reviews, 121(16), 10283–10331.
  9. [9] Zhu, X., Li, Y., & Zhang, J. (2020). pH-responsive mesoporous silica nanoparticles for drug delivery. Journal of Materials Chemistry B, 8(4), 726–742.
  10. [10] Thomas, M., Klibanov, A. M., & Langer, R. (2005). Poly(β-amino esters): Synthesis, characterization, and self-assembly with plasmid DNA. Journal of the American Chemical Society, 127(21), 7910–7918.
  11. [11] Lynn, D. M., & Langer, R. (2000). Synthesis of poly(β-amino esters) by the conjugate addition of primary and secondary amines to a bis(acrylate ester). Journal of the American Chemical Society, 122(47), 11818–11819.
  12. [12] Jayasurya, A., & Thomas, T. (2022). Aptamers: An emerging class of ligands for targeted drug delivery. Journal of Controlled Release, 342, 1078–1100.
  13. [13] Jayasena, S. D. (1999). Aptamers: An emerging class of molecules that rival antibodies in diagnostics. Clinical Chemistry, 45(9), 1628–1650.
  14. [14] Bates, P. J., Morris, K. V., Gallo, N. B., et al. (2009). Aptamers as targeted therapeutics: Current potential and challenges. Nature Reviews Drug Discovery, 8(7), 546–558.
  15. [15] Gu, F., Zhang, H., & Tan, W. (2019). AS1411 aptamer: A promising therapeutic agent for cancer treatment. Theranostics, 9(19), 5591–5604.
  16. [16] Peng, H., Zhang, Y., & Wang, Z. (2018). Nucleolin: A target for cancer therapy. Journal of Hematology & Oncology, 11(1), 124.
  17. [17] Liu, Y., Wang, X., & Li, X. (2023). Aptamer-functionalized mesoporous silica nanoparticles for targeted cancer therapy. Advanced Healthcare Materials, 12(5), 2201844.
  18. [18] Zhang, L., Chen, Y., & Liu, X. (2021). pH-responsive aptamer-conjugated mesoporous silica nanoparticles for targeted siRNA delivery to triple-negative breast cancer. Biomaterials, 273, 120834.
  19. [19] Wang, Z., Li, J., & Zhang, Q. (2020). Endosomal escape strategies for improving the efficacy of nucleic acid-based therapeutics. Advanced Drug Delivery Reviews, 164, 113–132.
  20. [20] Akinc, A., Thomas, M., Klibanov, A. M., et al. (2005). Poly(β-amino esters) and their use in drug delivery. Advanced Materials, 17(15), 1845–1850.
  21. [21] Song, E., Kim, S., & Lee, D. S. (2019). siRNA delivery systems for cancer therapy. Journal of Controlled Release, 304, 138–154.
  22. [22] Ghosh, P., & Han, G. W. (2021). Nanoparticle-mediated siRNA delivery for cancer therapy: Challenges and strategies. Journal of Biomedical Nanotechnology, 17(1), 1–26.
  23. [23] Mittal, S., Srivastava, S., & Maitra, A. (2020). Mesoporous silica nanoparticles: A versatile platform for drug delivery and biomedical applications. Current Pharmaceutical Design, 26(34), 4191–4210.
  24. [24] Huang, X., Zhang, Y., & Wang, H. (2022). Surface functionalization of mesoporous silica nanoparticles for targeted drug delivery. Chemical Engineering Journal, 442, 136164.
  25. [25] Li, Y., Zhu, X., & Zhang, J. (2021). Stimuli-responsive mesoporous silica nanoparticles for controlled drug release. Small, 17(2), 2004799.
  26. [26] Wang, H., Li, Y., & Zhang, Q. (2020). Aptamer-functionalized nanoparticles for targeted cancer therapy: A review. Biomedical Materials, 15(5), 052001.
  27. [27] Zhou, J., Li, J., & Wang, Z. (2019). pH-responsive polymers for drug delivery. Polymer Chemistry, 10(4), 405–422.
  28. [28] Cheng, C., Zhang, H., & Tan, W. (2020). Aptamers in cancer therapy: Current status and future perspectives. Trends in Pharmacological Sciences, 41(11), 852–867.
  29. [29] Zhang, Y., Peng, H., & Wang, Z. (2018). Nucleolin-targeted cancer therapy: A review. Cancer Letters, 430, 1–10.
  30. [30] Liu, X., Chen, Y., & Zhang, L. (2023). Triple-negative breast cancer: Current challenges and nanomedicine-based therapeutic strategies. Advanced Drug Delivery Reviews, 196, 114078.
  31. [31] Davis, M. E. (2014). The first targeted delivery of siRNA in humans via a self-assembling, cyclodextrin-containing polymer. Nature Biotechnology, 32(11), 1141–1142.
  32. [32] Shah, S., & Langer, R. (2014). RNA interference-based therapeutics and their delivery challenges. Advanced Drug Delivery Reviews, 66, 108–116.
  33. [33] Thomas, M., Klibanov, A. M., & Langer, R. (2007). Poly(β-amino esters) for nucleic acid delivery. Accounts of Chemical Research, 40(11), 1171–1179.
  34. [34] Gu, F., Zhang, H., & Tan, W. (2021). AS1411 aptamer-functionalized nanomaterials for cancer diagnosis and therapy. Chemical Society Reviews, 50(12), 6845–6872.
  35. [35] Wang, Y., Li, J., & Zhang, Q. (2022). Mesoporous silica nanoparticles in cancer therapy: A review. Journal of Materials Chemistry B, 10(1), 1–22.
  36. [36] Li, X., Liu, Y., & Wang, X. (2021). Targeted siRNA delivery using aptamer-functionalized mesoporous silica nanoparticles for cancer therapy. Bioconjugate Chemistry, 32(5), 1074–1085.
  37. [37] Chen, Y., Zhang, L., & Liu, X. (2020). MCL-1 as a therapeutic target in triple-negative breast cancer. Journal of Hematology & Oncology, 13(1), 142.
  38. [38] Opferman, J. T., & Letai, A. (2008). Diagnosing and targeting BCL-2 family proteins in cancer. Current Opinion in Pharmacology, 8(4), 412–419.
  39. [39] Tan, W., & Zhang, H. (2018). Aptamers: Powerful tools for biomedical research and therapy. Chemical Reviews, 118(12), 6419–6469.
  40. [40] Zhang, Q., Wang, Y., & Li, J. (2023). Nanoparticle-based siRNA delivery systems for triple-negative breast cancer: Recent advances and future perspectives. Advanced Healthcare Materials, 12(8), 2202445.