Nanoscale Drug Delivery Platforms for Pancreatic Ductal Adenocarcinoma Treatment

Abstract

Pancreatic ductal adenocarcinoma (PDAC) exhibits profound therapeutic resistance driven by a dense desmoplastic tumor microenvironment (TME). Orchestrated by cancer-associated fibroblasts (CAFs), this fibrotic matrix elevates interstitial fluid pressure and physically abolishes the extravasation of conventional chemotherapeutics. Nanomedicine offers a paradigm-shifting approach to dismantle these biophysical barriers. This review critically evaluates recent advancements in nanoscale delivery systems engineered specifically for PDAC. Moving beyond the ineffective enhanced permeability and retention (EPR) effect, we examine intelligent nanoplatforms capable of localized stroma remodeling, active receptor-mediated targeting, and stimuli-responsive payload release triggered by TME hallmarks. We also explore biomimetic carriers, such as exosomes and albumin-based platforms,  that exploit PDAC metabolic scavenging pathways while evading immune clearance. Finally, we address critical translational bottlenecks bridging preclinical success and clinical reality, prioritizing manufacturing scale-up, murine-to-human predictive disparities, and the delicate clinical balance between matrix remodeling and metastatic risk.