Biomimetic Nanodrug Prepared by Cell Exocytosis Induces Cancer Stem Cell Differentiation by Attenuating Wnt Signaling Pathway

Abstract Cancer stem cells (CSCs) represent a critical therapeutic target due to their role in chemoresistance and tumor recurrence. Targeting CSCs based on their distinct differentiation ability is a brilliant cancer therapeutic strategy. Although a few small‐molecule and nanomaterial‐based differentiation inducers have been reported, their limited specificity raises concerns about off‐target effects, particularly the unintended differentiation of normal stem cells. Recently, mesenchymal stem cell‐derived exosomes (MSC‐exos) have come into focus as drug carriers as they retain parental properties that can alter functionality of CSCs types and produce mature tumor cells. Herein, an in situ biosynthetic MSC‐exos‐based nanodrug (E‐DDP@MSNs) have been developed by incubating MSCs with cisplatin‐loaded mesoporous silica nanoparticles, which are then isolated from the cell culture medium by ultracentrifugation. In contrast to the electroporation, E‐DDP@MSNs retain the exosomal contents more completely without significant leakage that can promote the CSCs to differentiate into mature tumor cells, which are more susceptible to chemotherapy. Mechanistically, E‐DDP@MSN promotes the differentiation of CSCs by transporting exosomal DKK‐1 into CSCs, thereby causing attenuation of the Wnt pathway that is essential in maintaining stemness, self‐renewal, and tumorigenicity of CSCs. In summary, E‐DDP@MSNs represent a promising approach for CSC‐targeted differentiation therapy, offering high efficacy with minimal toxicity.