Nanomedicine Journal

Nanomedicine Journal

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

Document Type : Research Paper

Authors
Yue Gao 1
Xuelian Wang 2
Lei Cui 3
Pengcheng Li 1
Fang Wang 1
Baobao Fu 1
Chenchen Wang 1
Qianqian Jia 1
Hongjiang Zhang 1
Jin Wang 1
Yong Wang 1
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.
Keywords
Renal Cell Carcinoma
Drug Resistance
Nanoparticles
RNA, Small Interfering
Methyltransferases
Subjects
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Nanomedicine Journal
Volume 13, Issue 3
Summer 2026
Pages 430-441