piR‐RCC Suppresses Renal Cell Carcinoma Progression by Facilitating YBX‐1 Cytoplasm Localization

PIWI-interacting RNAs (piRNAs), a novel category of small non-coding RNAs, are widely expressed in eukaryotes and deregulated in several pathologies, including cancer. Little is known about their function and mechanism in renal cell carcinoma (RCC) progression. Herein, a down-regulated piRNA in RCC, termed piR-hsa-28489 (designated as piR-RCC), is identified to impede RCC progression both in vivo and in vitro. Mechanistically, piR-RCC directly interacts with Y-box binding protein 1 (YBX-1), thus impeding p-AKT-mediated YBX-1 phosphorylation and its subsequent nuclear translocation. Moreover, YBX-1 coordinates the transcription of ETS homologous factor (EHF) as a repressor factor. Consequently, piR-RCC enhances EHF expression, leading to the inhibition of RCC proliferation and metastasis. Based on these, a biomimetic nanoparticle platform is constructed to achieve RCC-specific targeted delivery of piR-RCC. The nanoparticles are fabricated using a cell membrane coating derived from cancer cells and used to encapsulate and deliver piR-RCC plasmids to renal orthotopic implantation in mice, hindering RCC progression. This study illustrates piR-RCC/YBX-1/EHF signaling axis in RCC, offering a promising therapeutic avenue for RCC.