Nucleus-targeted Silencer nanoplatform regulating ZEB1-AS1 in head and neck squamous cell carcinoma therapy

Long noncoding RNAs have emerged as key players in the progression of head and neck squamous cell carcinoma (HNSC). Among them, ZEB1-AS1 was identified as an upregulated candidate in HNSC through comprehensive analysis of RNA-sequencing datasets. Here, elevated ZEB1-AS1 expression was correlated with poor prognosis in HNSC patients. Further investigations demonstrated that downregulation of ZEB1-AS1 induced epithelial-mesenchymal transition and increased sensitivity to cisplatin in Cal27 cells, while its upregulation reversed these effects, underscoring its pivotal role in tumor metastasis and cisplatin resistance in Cal27 cells. Mechanistically, ZEB1-AS1, located in cytoplasm and nucleus, directly regulated the expression of ZEB1, thereby influencing the expression of mu opioid receptor (MOR) and implicating in cancer progression. To advance clinical translation, we employed a nucleus-targeting nanoparticle platform for efficient delivery of a mixture of antisense oligonucleotides and siRNA (Silencer), effectively manipulating ZEB1-AS1 expression in vitro and in vivo. Besides, a predictive model for HNSC patients was developed by analyzing the expression levels of ZEB1-AS1, ZEB1, and MOR in the HNSC datasets. Our study underscored the critical role of ZEB1-AS1 in HNSC and its potential as a therapeutic target. By elucidating its functional mechanisms and utilizing a nucleus-targeting nanoparticle platform for efficient delivery, we proved the potential of ZEB1-AS1-targeted therapies in HNSC.