Xing Liu,1 Yidan Shao,2 Yunjiang Li,3 Zuhua Chen,3 Tingting Shi,2 Qiao Tong,2 Xi Zou,2 Liping Ju,2 Jinming Pan,2 Rangxiao Zhuang,2,* Xuwang Pan2,* 

1School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, 311400, People’s Republic of China; 2Department of Pharmaceutical Preparation, Affiliated Hangzhou Xixi Hospital, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, 310023, People’s Republic of China; 3Radiology Department, Affiliated Hangzhou Xixi Hospital, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, 310023, People’s Republic of China

*These authors contributed equally to this work

Correspondence: Rangxiao Zhuang; Xuwang Pan, Department of Pharmaceutical Preparation, Affiliated Hangzhou Xixi Hospital, Zhejiang Chinese Medical University, 2, Hengbu Road, Hangzhou, Zhejiang, 310023, People’s Republic of China, Tel +86-571-8648-1609, Email zhuangrangxiao@sina.com; pxuwang@163.com

Abstract: Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest cancers in the world, mainly because of its powerful pro-connective tissue proliferation matrix and immunosuppressive tumor microenvironment (TME), which promote tumor progression and metastasis. In addition, the extracellular matrix leads to vascular collapse, increased interstitial fluid pressure, and obstruction of lymphatic return, thereby hindering effective drug delivery, deep penetration, and immune cell infiltration. Therefore, reshaping the TME to enhance tumor perfusion, increase deep drug penetration, and reverse immune suppression has become a key therapeutic strategy. Traditional therapies for PDAC, including surgery, radiation, and chemotherapy, face significant limitations. Surgery is challenging due to tumor location and growth, while chemotherapy and radiation are hindered by the dense extracellular matrix and immunosuppressive TME. In recent years, the advancement of nanotechnology has provided new opportunities to improve drug efficacy. Nanoscale drug delivery systems (NDDSs) provide several advantages, including improved drug stability in vivo, enhanced tumor penetration, and reduced systemic toxicity. However, the clinical translation of nanotechnology in PDAC therapy faces several challenges. These include the need for precise targeting and control over drug release, potential immune responses to the nanocarriers, and the scalability and cost-effectiveness of production. This article provides an overview of the latest nanobased methods for achieving better therapeutic outcomes and overcoming drug resistance. We pay special attention to TME-targeted therapy in the context of PDAC, discuss the advantages and limitations of current strategies, and emphasize promising new developments. By emphasizing the enormous potential of NDDSs in improving the treatment outcomes of patients with PDAC, while critically discussing the limitations of traditional therapies and the challenges faced by nanotechnology in achieving clinical breakthroughs, our review paves the way for future research in this rapidly developing field.

Keywords: nanoscale, drug delivery systems, pancreatic ductal adenocarcinoma, tumor microenvironment, deep penetration