Abundant desmoplastic stroma, which typically exists in pancreatic ductal adenocarcinoma (PDAC), can act as a natural protective physical barrier rendering insufficient drug delivery and penetration. To address this issue, we herein report a two-step sequential delivery strategy for enhanced pancreatic cancer therapy. In this sequential strategy, the nitric oxide (NO) donor S-nitroso-N-acetylpenicillamine (SNAP) loaded micelles (Lip-SNAP) were firstly delivered to pancreatic stellate cells (PSCs) in tumor tissue to inhibit the production of dense stroma, by inhibiting the expression of TGF-β1 and its downstream profibrotic signal transduction. Therefore, the PSC-mediated desmoplastic reaction could be suppressed by inhibiting the expression of fibronectin, α-SMA and collagen. The gemcitabine (GEM) loaded liposomes (Lip-GEM) were administrated subsequently. The enhanced intratumoral penetration of Lip-GEM was then achieved due to the stromal disruption in consequence of NO treatment, thus significantly improving the drug delivery efficiency. The tumor growth inhibition of the two-step sequential delivery of Lip-SNAP and Lip-GEM was investigated on both subcutaneous and orthotopic tumor mouse models, to show the remarkably improved therapeutic efficacy of GEM. Such NO-induced stromal depletion provides a general strategy to overcome the blockage of desmoplastic stroma on other therapeutic agents.

胰腺导管腺癌（PDAC）中通常存在大量的增生基质，可作为天然的保护性物理屏障，使药物的递送和渗透不足。为了解决这个问题，我们在此报告了一种用于增强胰腺癌治疗的两步顺序递送策略。在此顺序策略中，一氧化氮（NO）供体S-亚硝基首先，通过抑制TGF-β1的表达及其下游的纤维化信号转导，将负载有乙酰乙酰青霉胺（SNAP）的胶束（Lip-SNAP）递送至肿瘤组织中的胰腺星状细胞（PSC），以抑制致密基质的产生。因此，可以通过抑制纤连蛋白，α-SMA和胶原蛋白的表达来抑制PSC介导的增生反应。随后施用吉西他滨（GEM）负载的脂质体（Lip-GEM）。然后由于NO处理导致的基质破坏，实现了Lip-GEM的增强的肿瘤内渗透，从而显着提高了药物递送效率。在皮下和原位肿瘤小鼠模型上研究了Lip-SNAP和Lip-GEM两步顺序递送的肿瘤生长抑制作用，显示出GEM的显着改善的治疗功效。此类NO诱导的基质耗竭提供了克服其他药物对增生基质的阻滞的一般策略。