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Pancreatic cancer is one of the most lethal malignancies, with a 5-year survival rate of less than 10 %. One of the major challenges in treating pancreatic cancer is the dense stroma and extracellular matrix (ECM) that surrounds the tumor, which creates a physical barrier to drug delivery and promotes tumor progression. This rigid stroma limits the infiltration of cytotoxic immune cells and also the penetration of chemotherapeutic agents or other anticancer drugs like immune checkpoint blockers (ICBs). In recent years, nanoparticle-based targeting of the pancreatic tumor stroma and ECM has emerged as an encouraging approach to overcome these challenges and improve treatment outcomes. Nanoparticles are capable of crossing ECM and rigid stroma, thereby delivering antitumor drugs or cells into tumors. This review article provides an overview of the current state of research on nanoparticle-based targeting of pancreatic tumor stroma and ECM. It discusses the various types of nanoparticles that have been developed for this purpose, including liposomes, polymeric nanoparticles, and inorganic nanoparticles, as well as the different targeting strategies that have been employed, such as ligand-mediated targeting like nanoparticles loaded with peptides and small interference RNAs (siRNAs) and stimuli-responsive nanoparticles like acidic and hypoxic-responsive nanoparticles. This review article also discusses the challenges and future directions in this field, such as the need for a better understanding of the tumor stroma in pancreatic malignancies and the development of more effective targeting strategies.