Regulation of CAF by α-Mangostin Promotes the Penetration of Nanomedicine and Inhibits the Metastasis of Breast Tumor

In the treatment of breast cancer, loading chemotherapy drugs into nanoparticles can accumulate in tumor tissues by virtue of the enhanced permeability and retention (EPR) effect, thereby reducing the systemic toxicity of chemotherapy drugs and improving the therapeutic effect. However, the interior of solid tumors contains a dense extracellular matrix (ECM) composed largely of cancer-associated fibroblasts (CAFs), which severely hinders the deep penetration of drugs and limits their full therapeutic efficacy. Although the antifibrotic effects of α-mangostin (α-M) have been reported, its potential in remodeling the tumor microenvironment (TME) to synergistically enhance nanomedicine penetration and antimetastatic efficacy remains underexplored. For this reason, our study proposes a combined therapeutic strategy that inhibits the activity of CAFs through the antifibrotic drug α-mangostin, in order to promote better penetration of shikonin nanomedicine (NP/SHK) into the tumor tissue and enhance the therapeutic effect of breast cancer. Chitosan thermosensitive hydrogel loaded with α-M (HG@α-M) is designed to transform CAFs from an activated state to a quiescent state and reduce the deposition of ECM. In addition, we designed glutathione (GSH)-responsive nanomedicine (NP/SHK) carrying shikonin (SHK), which solves the problem of poor water solubility of SHK itself. In breast cancer model mice, compared with the single NP/SHK treatment group, the combined treatment down-regulated the expressions of CAF markers α-SMA and FAP-α by 52.70 and 56.77%, respectively, increased the tumor growth inhibition rate by 32.27%, and reduced lung metastatic nodules by 26.06%. This study effectively inhibited the growth and metastasis of tumors, providing a new and efficient combined treatment approach for metastatic breast cancer.