Crumpled Aluminum Hydroxide Nanostructures as a Microenvironment Dysregulation Agent for Cancer Treatment

Owing to their unique physicochemical properties, nanomaterials have become a focus of multidisciplinary research efforts including investigations of their interactions with tumor cells and stromal compartment of tumor microenvironment (TME) toward the development of next-generation anticancer therapies. Here, we report that agglomerates of radially assembled Al hydroxide crumpled nanosheets exhibit anticancer activity due to their selective adsorption properties and positive charge. This effect was demonstrated in vitro by decreased proliferation and viability of tumor cells, and further confirmed in two murine cancer models. Moreover, Al hydroxide nanosheets almost completely inhibited the growth of murine melanoma in vivo in combination with a minimally effective dose of doxorubicin. Our direct molecular dynamics simulation demonstrated that Al hydroxide nanosheets can cause significant ion imbalance in the living cell perimembranous space through the selective adsorption of extracellular anionic species. This approach to TME dysregulation could lay the foundation for development of novel anticancer therapy strategies.