Dual-Responsive Micelles Co-delivering All-Trans Retinoic Acid and Paclitaxel for Enhanced Eradication of Osteosarcoma Stem Cells

Osteosarcoma is the most prevalent primary bone cancer affecting children and adolescents, characterized by its high invasiveness and the challenges in treatment posed by multidrug resistance. Cancer stem cells significantly contribute to poor clinical outcomes; however, current targeted therapies remain limited in their effectiveness. In this study, we developed a novel dual-responsive nanomedicine designed to target the microenvironment of osteosarcoma cancer stem cells (OCSCs) and osteosarcoma itself, which selectively releases all-trans retinoic acid and paclitaxel, termed mPCDAP. Our findings indicate that mPCDAP rapidly releases all-trans retinoic acid to suppress stemness under conditions of elevated glutathione, subsequently increasing intracellular reactive oxygen species levels in tumor cells. This mechanism further facilitates the release of paclitaxel under conditions of highly reactive oxygen species, thereby inducing apoptosis in osteosarcoma cells. Additionally, mPCDAP was effectively internalized by both osteosarcoma cells and OCSCs, with in vitro and in vivo results demonstrating significant synergistic antitumor effects, promoting apoptosis and markedly reducing tumor stemness. This study presents a novel approach and promising prospects for targeted therapy of osteosarcoma and OCSCs.