Hyaluronic acid-modified PLGA nanoparticles encapsulating METTL۱۴ siRNA enhance sunitinib sensitivity in drug-resistant renal cell carcinoma

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 ۱۴ (METTL۱۴), 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 METTL۱۴ siRNA. Their physicochemical characteristics, targeting capability toward CD۴۴-positive sunitinib-resistant RCC cells (۷۸۶-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 (>۸۸%), along with favorable stability. HA modification significantly improved cellular uptake in CD۴۴-positive resistant cells compared with non-targeted nanoparticles. Delivery of METTL۱۴ siRNA via HA-PLGA-NPs markedly reduced the IC۵۰ of sunitinib, increased apoptotic cell death, and effectively reversed drug resistance. In vivo, treatment with HA-PLGA (METTL۱۴ siRNA)-NPs led to substantial tumor growth inhibition. RNA sequencing indicated that METTL۱۴ 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 METTL۱۴ 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.

کلیدواژه ها:

Renal cell carcinoma ، Drug resistance ، Nanoparticles ، RNA ، Small Interfering ، Methyltransferases