Nanoparticle encapsulated CQ/TAM combination harmonizes with MSCs in arresting progression of severity in AP mice through iNOS (IDO) signaling

Background: Sever acute pancreatitis (SAP) is a critical disease with high mortality, and lack of clinically available treatments with specificity and effectiveness. Bone marrow derived mesenchymal stem cells (BMSCs) exhibited moderate effect on AP which needs further improvement. Methods: Pancreatic infiltrating lymphocytes were analyzed to demonstrate the intervention of BMSCs on inflammatory cell infiltration of AP. Gene silencing with siRNA and small molecule inhibitor were utilized to determine the key effector molecule of BMSCs on AP. Pharmacological regulation and nanotechnology were introduced to further ameliorate BMSCs action. Results: It was revealed that BMSCs prevent the progression of acute pancreatitis (AP) by reducing recruitment of macrophages, neutrophils and CD4+T cells in the lesion site. The pivotal role of chemokine-iNOS-IDO axis for BMSCs to intervene AP was confirmed. Compared with any single drug, Chloroquine/Tamoxifen combination together with IFN-γ pronouncedly up-regulated the transcription of several MSC immune regulators such as COX-2, PD-L1, HO-1 especially iNOS/IDO. As expected, BMSCs and human umbilical cord mesenchymal stem cells (UMSCs) pretreated with CQ/TAM/IFN-γ exerted enhanced intervention in AP and SAP mice. Moreover, pretreatment with CQ-LPs/TAM-NPs combination not only counteracted MSCs proliferation inhibition induced by free drugs but also enhanced their efficacy. Conclusion: Under the background of rapid progress in MSCs clinical translation, this study focuses on the urgent clinical issue and initiates an original mechanism-based strategy to promote intervention on severity progression of SAP, which promises its clinical translation in future.