Pancreatic ductal adenocarcinoma (PDAC) is one of the most intractable malignancy, with an only 6% 5-year relative survival rate. The dismal therapeutic effect is attributed to the chemotherapy resistance and unique pathophysiology with abundant inflammatory cytokines and abnormal hyperplasia of extracellular matrix (ECM). Based on the theory that bone marrow mesenchymal stem cells (BM-MSCs) can influence the tumorous microenvironment and malignant growth of PDAC, we employed exosomes (Exos) derived from BM-MSCs as PDAC-homing vehicles to surpass the restrictions of pathological ECM and increase the accumulation of therapeutics in tumor site. To overcome chemoresistance of PDAC, paclitaxel (PTX) and gemcitabine monophosphate (GEMP)—an intermediate product of gemcitabine metabolism—were loaded in/on the purified Exos. In this work, the Exo delivery platform showed superiorities in homing and penetrating abilities, which were performed on tumor spheroids and PDAC orthotopic models. Meanwhile, the favorable anti-tumor efficacy in vivo and in vitro, plus relatively mild systemic toxicity, was found. Loading GEMP and PTX, benefitting from the naturally PDAC selectivity, the Exo platform we constructed performs combined functions on excellent penetrating, anti-matrix and overcoming chemoresistance (Scheme 1). Worth expectantly, the Exo platform may provide a prospective approach for targeted therapies of PDAC.

胰腺导管腺癌（PDAC）是最难治的恶性肿瘤之一，其5年相对生存率仅为6％。令人沮丧的治疗效果归因于化疗耐药性和独特的病理生理学，具有丰富的炎性细胞因子和细胞外基质（ECM）异常增生。基于骨髓间充质干细胞（BM-MSC）可以影响PDAC的肿瘤微环境和恶性生长的理论，我们采用源自BM-MSC的外泌体（Exos）作为PDAC归巢载体，以克服病理性ECM和增加治疗剂在肿瘤部位的蓄积。为了克服PDAC的化学耐药性，将紫杉醇（PTX）和吉西他滨单磷酸（GEMP）（吉西他滨代谢的中间产物）装在纯化的Exos中/上。在这项工作中，Exo递送平台在归巢和穿透能力方面表现出优势，这是在肿瘤球体和PDAC原位模型上进行的。同时，良好的抗肿瘤功效发现体内和体外，以及相对轻度的全身毒性。加载GEMP和PTX，得益于自然的PDAC选择性，我们构建的Exo平台具有出色的渗透性，抗基质和克服化学抗性的组合功能（方案1）。值得期待的是，Exo平台可能为PDAC的靶向治疗提供了一种前瞻性方法。