CAFs targeted ultrasound-responsive nanodroplets loaded V9302 and GLULsiRNA to inhibit melanoma growth via glutamine metabolic reprogramming and tumor microenvironment remodeling

Despite rapid advances in metabolic therapies over the past decade, their efficacy in melanoma has been modest, largely due to the interaction between cancer-associated fibroblasts (CAFs) and cancer cells to promote cancer growth. Altering the tumor microenvironment (TME) is challenging and elusive. CAFs is critical for glutamine deprivation survival in melanoma. In this research, we assembled a CAFs-targeted, controlled-release nanodroplets for the combined delivery of the amino acid transporter ASCT2 (SLC1A5) inhibitor V9302 and GLULsiRNA (siGLUL). The application of ultrasound-targeted microbubble disruption (UTMD) allows for rapid release of V9302 and siGLUL, jointly breaking the glutamine metabolism interaction between CAFs and cancer cells on one hand, on the other hand, blocking activated CAFs and reducing the expression of extracellular matrix (ECM) to facilitate drug penetration. In addition, ultrasound stimulation made siGLUL more accessible to tumor cells and CAFs, downregulating GLUL expression in both cell types. FH-V9302-siGLUL-NDs also serve as contrast-enhanced ultrasound imaging agents for tumor imaging. Our study developed and reported FH-NDs as nanocarriers for V9302 and siGLUL, demonstrating that FH-V9302-siGLUL-NDs have potential bright future applications for integrated diagnostic therapy.

Automated summary

Despite advances in metabolic therapies, their efficacy in melanoma is limited due to the interaction between cancer-associated fibroblasts (CAFs) and cancer cells. This study developed a CAFs-targeted nanodroplet system for the delivery of ASCT2 inhibitor and GLUL siRNA. Ultrasound-targeted microbubble disruption was used to facilitate drug release and block the interaction between CAFs and cancer cells. The nanodroplets also served as contrast agents for tumor imaging.