pH-responsive morphological transition: Peptide amphiphile-based nanovehicles inhibit drug efflux and modulate cancer-associated fibroblasts to combat bladder cancer

The tumor microenvironment (TME) presents significant challenges for effective drug delivery in bladder cancer treatment. The dense extracellular matrix (ECM) and cancer-associated fibroblasts (CAFs) in the TME impede drug penetration and transport efficiency. Additionally, the mucosal barrier of the bladder obstructs drug absorption, while urine flow around the tumor leads to a gradual decrease in drug concentration. We aimed to enhance the targeted delivery of silybin (SLB) and cisplatin (DDP) using the formulation DS/Pep. This drug-carrying vehicle was designed to exploit the enhanced permeability and retention (EPR) effect typical of solid tumors and active targeting. Notably, DS/Pep can transition from spherical nanoparticles to high aspect ratio aggregates in slightly acidic environments, increasing drug accumulation at the tumor site. In an in vitro coculture system of MB49 bladder cancer cells and NIH 3T3 fibroblasts that mimics the tumor microenvironment, DS/Pep effectively reduced CAF activation. In vivo , DS/Pep effectively reduced the expression of CAF biomarkers and collagen, improved tissue permeability, and inhibited tumor growth and metastasis. DS/Pep also indirectly affected the tumor immune microenvironment by suppressing CAF activation, thereby modulating the immunological status of the premetastatic niche. Overall, this study presents a promising approach for enhancing bladder cancer treatment via targeted drug delivery, underscoring the potential of DS/Pep in overcoming the barriers posed by the TME.