Overcoming the tumor microenvironment in pancreatic cancer via barrier-specific nanoparticle drug delivery

Pancreatic cancer is one of the most lethal malignancies, largely due to the formidable pathophysiological barriers presented by its tumor microenvironment (TME). These include metabolic stress, such as acidosis and elevated reactive oxygen species; dense stromal architecture with poor perfusion; and profound immune suppression, all of which severely limit drug delivery and therapeutic efficacy. Recent advances in nanomedicine have enabled the development of TME-responsive drug delivery systems (DDSs) capable of targeting these distinct barriers. This review outlines three major TME-derived barriers in pancreatic cancer and presents emerging nanoparticle-based strategies to overcome them. Specifically, we discuss the use of pH- and ROS-responsive nanoparticles to address metabolic stress, penetration-enhancing nanocarriers to navigate physical stromal obstacles, and immune-modulatory nanoparticle systems to restore antitumor immunity. Finally, we highlight the future potential of integrating artificial intelligence with nanomedicine to design personalized, multifunctional DDSs tailored to the heterogeneous TME. These advances collectively suggest that TME-responsive nanodelivery offers significant promise for transforming the treatment landscape of pancreatic cancer.