Hyaluronic acid-modified PLGA nanoparticles encapsulating METTL14 siRNA enhance sunitinib sensitivity in drug-resistant renal cell carcinoma

Articles in Press

Document Type : Research Paper

Authors

1 Department of Oncology, The First Affiliated Hospital of Anhui University of Science and Technology (Huainan First People's Hospital), Huainan, China

2 Department of Neurology, The First Affiliated Hospital of Anhui University of Science and Technology (Huainan First People's Hospital), Huainan, China

3 Department of Hepatobiliary Surgery, The First Affiliated Hospital of Anhui University of Science and Technology (Huainan First People's Hospital), Huainan, China

10.22038/nmj.2026.92437.2344

Abstract

Objective(s): Sunitinib resistance remains a major obstacle in the treatment of renal cell carcinoma (RCC). This study sought to construct a targeted nanoparticle-based delivery system for silencing methyltransferase-like 14 (METTL14), with the aim of restoring drug responsiveness in resistant RCC.
Methods: Hyaluronic acid-functionalized poly (lactic-co-glycolic acid) nanoparticles (HA-PLGA-NPs) were engineered to encapsulate METTL14 siRNA. Their physicochemical characteristics, targeting capability toward CD44-positive sunitinib-resistant RCC cells (786-O-SUR and ACHN-SUR), and therapeutic performance were systematically evaluated in vitro. Transcriptomic analysis was conducted to investigate underlying mechanisms. Antitumor efficacy and biosafety were further examined in a xenograft mouse model.
Results: The fabricated nanoparticles displayed uniform morphology, appropriate particle size, and high siRNA encapsulation efficiency (>88%), along with favorable stability. HA modification significantly improved cellular uptake in CD44-positive resistant cells compared with non-targeted nanoparticles. Delivery of METTL14 siRNA via HA-PLGA-NPs markedly reduced the IC50 of sunitinib, increased apoptotic cell death, and effectively reversed drug resistance. In vivo, treatment with HA-PLGA (METTL14 siRNA)-NPs led to substantial tumor growth inhibition. RNA sequencing indicated that METTL14 silencing was associated with pathways involved in apoptosis, cell cycle regulation, and immune-related processes. No obvious systemic toxicity was observed.
Conclusion: HA-PLGA nanoparticles provide an effective and selective platform for METTL14 siRNA delivery, enabling reversal of sunitinib resistance in RCC models. This approach offers a potential therapeutic strategy for overcoming drug resistance in renal cell carcinoma.

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Main Subjects

References

  1. Young M, Jackson-Spence F, Beltran L, Day E, Suarez C, Bex A, et al. Renal cell carcinoma. Lancet. 2024;404(10451):476-491.
  2. Rose TL, Kim WY. Renal Cell Carcinoma: A Review. JAMA. 2024;332(12):1001-1010.
  3. Das A, Shapiro DD, Craig JK, Abel EJ. Understanding and integrating cytoreductive nephrectomy with immune checkpoint inhibitors in the management of metastatic RCC. Nat Rev Urol. 2023;20(11):654-668.
  4. Mollica V, Massari F. Adjuvant treatment in renal cell carcinoma: a never-ending story? Lancet. 2024;403(10425):433-434.
  5. Atkins MB, Gravis G, Drosik K, Demkow T, Tomczak P, Wong SS, et al. Trebananib (AMG 386) in Combination With Sunitinib in Patients With Metastatic Renal Cell Cancer: An Open-Label, Multicenter, Phase II Study. J Clin Oncol. 2015;33(30):3431-3438.
  6. Jin J, Xie Y, Zhang JS, Wang JQ, Dai SJ, He WF, et al. Sunitinib resistance in renal cell carcinoma: From molecular mechanisms to predictive biomarkers. Drug Resist Updat. 2023;67:100929.
  7. An Y, Duan H. The role of m6A RNA methylation in cancer metabolism. Mol Cancer. 2022;21(1):14.
  8. Guan Q, Lin H, Miao L, Guo H, Chen Y, Zhuo Z, et al. Functions, mechanisms, and therapeutic implications of METTL14 in human cancer. J Hematol Oncol. 2022;15(1):13.
  9. Chen Y, Lu Z, Qi C, Yu C, Li Y, Huan W, et al. N(6)-methyladenosine-modified TRAF1 promotes sunitinib resistance by regulating apoptosis and angiogenesis in a METTL14-dependent manner in renal cell carcinoma. Mol Cancer. 2022;21(1):111.
  10. Moazzam M, Zhang M, Hussain A, Yu X, Huang J, Huang Y. The landscape of nanoparticle-based siRNA delivery and therapeutic development. Mol Ther. 2024;32(2):284-312.
  11. Byeon Y, Lee JW, Choi WS, Won JE, Kim GH, Kim MG, et al. CD44-Targeting PLGA Nanoparticles Incorporating Paclitaxel and FAK siRNA Overcome Chemoresistance in Epithelial Ovarian Cancer. Cancer Res. 2018;78(21):6247-6256.
  12. Papanastasiou AD, Peroukidis S, Sirinian C, Arkoumani E, Chaniotis D, Zizi-Sermpetzoglou A. CD44 Expression in Clear Cell Renal Cell Carcinoma (ccRCC) Correlates with Tumor Grade and Patient Survival and Is Affected by Gene Methylation. Genes (Basel). 2024;15(5).
  13. Hou X, Yang C, Zhang L, Hu T, Sun D, Cao H, et al. Killing colon cancer cells through PCD pathways by a novel hyaluronic acid-modified shell-core nanoparticle loaded with RIP3 in combination with chloroquine. Biomaterials. 2017;124:195-210.
  14. Han HD, Mangala LS, Lee JW, Shahzad MM, Kim HS, Shen D, et al. Targeted gene silencing using RGD-labeled chitosan nanoparticles. Clin Cancer Res. 2010;16(15):3910-3922.
  15. Livney YD, Assaraf YG. Rationally designed nanovehicles to overcome cancer chemoresistance. Adv Drug Deliv Rev. 2013;65(13-14):1716-1730.
  16. Collins MN, Birkinshaw C. Hyaluronic acid based scaffolds for tissue engineering--a review. Carbohydr Polym. 2013;92(2):1262-1279.
  17. Hardingham TE, Muir H. The specific interaction of hyaluronic acid with cartillage proteoglycans. Biochim Biophys Acta. 1972;279(2):401-405.
  18. Yang B, Yang BL, Savani RC, Turley EA. Identification of a common hyaluronan binding motif in the hyaluronan binding proteins RHAMM, CD44 and link protein. EMBO J. 1994;13(2):286-296.
  19. Sendinc E, Shi Y. RNA m6A methylation across the transcriptome. Mol Cell. 2023;83(3):428-441.
  20. Shi H, Wei J, He C. Where, When, and How: Context-Dependent Functions of RNA Methylation Writers, Readers, and Erasers. Mol Cell. 2019;74(4):640-650.
  21. Sparmann A, Vogel J. RNA-based medicine: from molecular mechanisms to therapy. EMBO J. 2023;42(21):e114760.
  22. Pecot CV, Calin GA, Coleman RL, Lopez-Berestein G, Sood AK. RNA interference in the clinic: challenges and future directions. Nat Rev Cancer. 2011;11(1):59-67.
  23. Silva J, Chang K, Hannon GJ, Rivas FV. RNA-interference-based functional genomics in mammalian cells: reverse genetics coming of age. Oncogene. 2004;23(51):8401-8409.
  24. Adams D, Gonzalez-Duarte A, O'Riordan WD, Yang CC, Ueda M, Kristen AV, et al. Patisiran, an RNAi Therapeutic, for Hereditary Transthyretin Amyloidosis. N Engl J Med. 2018;379(1):11-21.
  25. Pastor F, Berraondo P, Etxeberria I, Frederick J, Sahin U, Gilboa E, et al. An RNA toolbox for cancer immunotherapy. Nat Rev Drug Discov. 2018;17(10):751-767.
  26. Shankar P, Manjunath N, Lieberman J. The prospect of silencing disease using RNA interference. JAMA. 2005;293(11):1367-1373.
  27. Rietwyk S, Peer D. Next-Generation Lipids in RNA Interference Therapeutics. ACS Nano. 2017;11(8):7572-7586.
  28. Charbe NB, Amnerkar ND, Ramesh B, Tambuwala MM, Bakshi HA, Aljabali AAA, et al. Small interfering RNA for cancer treatment: overcoming hurdles in delivery. Acta Pharm Sin B. 2020;10(11):2075-2109.
  29. Acharya S, Sahoo SK. PLGA nanoparticles containing various anticancer agents and tumour delivery by EPR effect. Adv Drug Deliv Rev. 2011;63(3):170-183.
  30. Goa KL, Benfield P. Hyaluronic acid. A review of its pharmacology and use as a surgical aid in ophthalmology, and its therapeutic potential in joint disease and wound healing. Drugs. 1994;47(3):536-566.
  31. Ge X, Li M, Yin J, Shi Z, Fu Y, Zhao N, et al. Fumarate inhibits PTEN to promote tumorigenesis and therapeutic resistance of type2 papillary renal cell carcinoma. Mol Cell. 2022;82(7):1249-1260.
  32. Xiong W, Zhang B, Yu H, Zhu L, Yi L, Jin X. RRM2 Regulates Sensitivity to Sunitinib and PD-1 Blockade in Renal Cancer by Stabilizing ANXA1 and Activating the AKT Pathway. Adv Sci (Weinh). 2021;8(18):e2100881.
  33. Sun Y, Zhu L, Liu P, Zhang H, Guo F, Jin X. ZDHHC2-Mediated AGK Palmitoylation Activates AKT-mTOR Signaling to Reduce Sunitinib Sensitivity in Renal Cell Carcinoma. Cancer Res. 2023;83(12):2034-2051.
  34. Li JY, Ren YP, Yuan Y, Ji SM, Zhou SP, Wang LJ, et al. Preclinical PK/PD model for combined administration of erlotinib and sunitinib in the treatment of A549 human NSCLC xenograft mice. Acta Pharmacol Sin. 2016;37(7):930-940.
  35. Qi X, Yang M, Ma L, Sauer M, Avella D, Kaifi JT, et al. Synergizing sunitinib and radiofrequency ablation to treat hepatocellular cancer by triggering the antitumor immune response. J Immunother Cancer. 2020;8(2).

 

Nanomedicine Journal

Articles in Press, Accepted Manuscript
Available Online from 25 May 2026

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