Novel nanotherapeutic strategy targeting mechanical tumor microenvironment in bladder cancer.

Abstract

This study investigated the mechanistic role of mechanical stress (MS) induced by partial bladder outlet obstruction (pBOO) in promoting bladder cancer (BC) growth and metastasis through single-cell RNA sequencing (scRNA-seq) and RNA sequencing (RNA-seq) techniques. An orthotopic BC mouse model subjected to pBOO was utilized to replicate contractile stress linked to lower urinary tract obstruction, with in vitro models providing supplementary insights into MS effects on BC malignancy. Exploratory scRNA-seq analysis suggested distinct epithelial subpopulations with elevated mechanical stress scores, while RNA-seq highlighted the prominent activation of the YAP/TAZ/AXL signaling axis by MS. Additionally, a CD44-targeted polymer-chitosan-lipid nanoparticle (PCL-NP@VP/siYAP) was developed for the concurrent delivery of Verteporfin and YAP-targeting siRNA to counteract the mechanical tumor microenvironment. The nanoparticles demonstrated favorable particle characteristics, enhanced cellular uptake in high CD44-expressing cells, and potent inhibitory effects on migration, invasion, and epithelial-mesenchymal transition in BC cells. Long-term in vivo imaging illustrated sustained accumulation of PCL-NP@VP/siYAP in orthotopic bladder tumors, leading to diminished tumor volume and distant metastases. Ultimately, this nanotherapeutic approach effectively disrupted the YAP/TAZ/AXL axis, reversing the mechanical tumor microenvironment induced by pBOO-associated MS and presenting a promising strategy to impede BC progression and metastasis.