Silencing MUC1 to regulate intracellular lipid metabolism: Overcoming sunitinib resistance and inhibiting metastasis in renal cell carcinoma

Renal cell carcinoma (RCC) has been extensively studied and is a paradigmatic example of a malignancy distinguished by metabolic reprogramming. Reprogramming lipid metabolism is crucial for determining the response and resistance to chemotherapy. To overcome this, we developed a modified nanomicelle delivery system comprising polyethyleneimine (PEI) as a positive charge donor and ibuprofen as the hydrophobic end. The overall system, denoted as SPPI, is PEGylated, conjugated with sialic acid, and plays a targeting role. This system successfully delivered siRNA to cancer cells by overcoming systemic and cellular barriers. The resulting conjugates form uniform, spherical nanomicelles (37.8 ± 0.9 nm; 25.5 ± 1.4 mV) with targeting ability, stability, efficient delivery, and low toxicity. The complicated and indirect way cholesterol affects ATP-binding cassette transporters was investigated. Administering SPPI/siMUC1 resulted in significant suppression of MUC1 expression and a 3.25-fold decrease in cholesterol synthesis compared to the control, and it subsequently reversed resistance to sunitinib by modulating P-GP, ABCG2, and MRP1 activities. Importantly, SPPI/siMUC1 nanomicelles demonstrated outstanding growth inhibition (72.2 %) of sunitinib-resistant 786-O cell xenografts and remarkable inhibitory effects on tumor metastasis (45.0 %) without observable systemic toxicity according to tissue analysis and weight change evaluation. The efficacy and safety of SPPI/siMUC1 in the treatment of ccRCC were demonstrated, especially after drug resistance develops. Thus, this study introduces a novel strategy for addressing drug resistance in metabolically active cancers by targeting the lipid metabolism pathway.