Membrane-Cloaked Nanodrug for Homologous Targeting and Treatment of Therapeutic Stress Escaped Cancer Stem Cells

Cancer stem cells (CSCs) often exhibit high expression of the p38/MAPK signaling pathway during therapy, leading to therapeutic stress-induced cellular escape (TSCE) and presenting a significant barrier to cancer treatment. Therefore, blocking the stress escape of CSCs or simultaneously targeting stress-escaping cells (TSCSCs) has become a crucial strategy in cancer therapy. However, the lack of specific markers for identifying TSCSCs has greatly limited the development of effective treatments. Cancer cell membranes exhibit selective binding and internalization by similar cancer cells. Herein, we report a nanoparticle with Fe 3 O 4 @SiO 2 as the core, which serves as a carrier to load the p38 inhibitor and is subsequently coated with homologous CSCs membranes. Herein, we reported a CSC membrane-coated nanoparticles that effectively targeted to homologous cancer cells while minimizing off-target effects, inhibited TSCE and tumor growth by introducing p38 inhibitor and thermotherapy. The application of this nanomaterial holds promise in overcoming current treatment challenges and providing strategies for cancer therapy. Fluorescence colocalization and in vivo imaging demonstrate that this nanoparticle effectively targets TSCSCs homogeneously while minimizing off-target effects. Transwell and QPCR analyses show that this nanoparticle inhibits the motility of BCSCs by preventing microtubule reorganization, thereby limiting their therapeutic stress escape from TSCE. Additionally, by introducing the p38 inhibitor, the tumor growth was significantly inhibited through suppressing the p38/MAPK signaling pathway. The application of this nanomaterial holds promise in overcoming current treatment challenges and providing strategies for cancer therapy.