Nano-delivery of salvianolic acid B induces the quiescence of tumor-associated fibroblasts via interfering with TGF-β1/Smad signaling to facilitate chemo- and immunotherapy in desmoplastic tumor

As the key stromal cells that mediate the desmoplastic reaction, tumor-associated fibroblasts (TAFs) play a critical role in the limited nanoparticle penetration and suppressive immune tumor microenvironment. Herein, we found that salvianolic acid B-loaded PEGylated liposomes (PEG-SAB-Lip) can interfere with the activation of TAFs by inhibiting the secretion of TGF-β1. After inhibiting the activation of TAFs, collagen deposition in tumors was reduced, and the penetration of nanoparticles in tumors was enhanced. The results of RT-qPCR and immunofluorescence staining showed the high expression of Th1 cytokines and chemokines (CXCL9 and CXCL10) and the recruitment of CD4+, CD8+ T cells, and M1 macrophages in the tumor area. At the same time, the low expression of Th2 cytokine and chemokine CXCL13, as well as the decrease of MDSCs, Tregs, and M2 macrophages were also observed in the tumor area. These results were related to the inactivation of TAFs. The combined treatment of PEG-SAB-Lip and docetaxel-loaded PEG-modified liposomes (PEG-DTX-Lip) can significantly inhibit tumor growth. Moreover, PEG-SAB-Lip further inhibited tumor metastasis to the lung. Therefore, our results showed that PEG-SAB-Lip can remodel the tumor microenvironment and improve the efficacy of nanoparticles.