胰腺癌中的多药耐药性在临床治疗中存在重大挑战。蟾蜍腺体分泌物中发现的一种化合物乌药酚（BA）可能有助于克服这个问题。然而，严重的心脏毒性迄今为止阻碍了其临床应用。因此，本研究旨在开发一种细胞膜伪装和负载BA的聚乳酸-聚乙二醇酸纳米颗粒（CBAP），并评估它在胰腺癌化疗耐药性中的潜力。通过心电图、体重、痛苦评分和小鼠的筑巢行为评估CBAP的毒性。此外，还在体外和体内研究了CBAP的抗癌活性和潜在机制。CBAP显著减轻了BA介导的急性心脏毒性，并增强了胰腺癌对多种临床药物（如吉西他滨、5-氟尿嘧啶和FOLFIRINOX）的敏感性。在机制上，CBAP直接结合到含有核苷酸结合和寡聚化结构域蛋白2（NOD2）的蛋白上，并抑制了核因子κ-轻链增强剂激活的B细胞的表达。这抑制了ATP结合盒转运蛋白的表达，这些蛋白负责癌细胞的耐药性。我们的研究结果表明，CBAP直接抑制NOD2。将CBAP与标准护理化疗药物结合使用代表了胰腺癌治疗的安全和高效策略。版权所有©2023年作者。由Elsevier Ltd.出版。保留所有权利。

Multidrug resistance in pancreatic cancer poses a significant challenge in clinical treatment. Bufalin (BA), a compound found in secretions from the glands of toads, may help overcome this problem. However, severe cardiotoxicity thus far has hindered its clinical application. Hence, the present study aimed to develop a cell membrane-camouflaged and BA-loaded polylactic-co-glycolic acid nanoparticle (CBAP) and assess its potential to counter chemoresistance in pancreatic cancer.The toxicity of CBAP was evaluated by electrocardiogram, body weight, distress score, and nesting behavior of mice. In addition, the anticarcinoma activity and underlying mechanism were investigated both in vitro and in vivo.CBAP significantly mitigated BA-mediated acute cardiotoxicity and enhanced the sensitivity of pancreatic cancer to several clinical drugs, such as gemcitabine, 5-fluorouracil, and FOLFIRINOX. Mechanistically, CBAP directly bound to nucleotide-binding and oligomerization domain containing protein 2 (NOD2) and inhibited the expression of nuclear factor kappa-light-chain-enhancer of activated B cells. This inhibits the expression of ATP-binding cassette transporters, which are responsible for chemoresistance in cancer cells.Our findings indicate that CBAP directly inhibits NOD2. Combining CBAP with standard-of-care chemotherapeutics represents a safe and efficient strategy for the treatment of pancreatic cancer.Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.