Display omitted •PDAC is a highly aggressive cancer exhibiting high mortality, that has not significantly improved over decades.•Nanomaterials have great potential to improve the dismal prognosis of PDAC.•We summarize the innovative use of nanoparticles to overcome the limitations of current treatments towards PDAC.•We describe the use of nanoparticles for the delivery of single and combinatory agents, for stroma-modulation therapies, and improved immunotherapy against PDAC. Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest cancers due to its aggressiveness and the challenges for early diagnosis and treatment. Recently, nanotechnology has demonstrated relevant strategies to overcome some of the major clinical issues in the treatment of PDAC. This review is focused on the pathological hallmarks of PDAC and the impact of nanotechnology to find solutions. It describes the use of nanoparticle-based systems designed for the delivery of chemotherapeutic agents and combinatorial alternatives that address the chemoresistance associated with PDAC, the development of combination therapies targeting the molecular heterogeneity in PDAC, the investigation of novel therapies dealing with the improvement of immunotherapy and handling the desmoplastic stroma in PDAC by remodeling the tumor microenvironment. A special section is dedicated to the design of nanoparticles for unique non-traditional modalities that could be promising in the future for the improvement in the dismal prognosis of PDAC.