Cascade-Targeting Nanoparticles for Reversing Chemoresistance in Osteosarcoma

Osteosarcoma is the most common primary malignant bone tumor in adolescents. Despite significant progress in multimodal therapies, its clinical efficacy remains severely limited by chemotherapy resistance. To overcome the barriers of DNA repair and drug efflux associated with resistance, we developed a biomimetic nanoplatform with cascade targeting capability, termed TAT-mPDO@cRGD-M. This system employs a polydopamine (mPDA) core with strong photothermal conversion and drug-loading capacity to co-deliver cisplatin and the PARP inhibitor olaparib. The surface is functionalized with a nuclear localization peptide (TAT) and cloaked with homologous osteosarcoma cell membranes modified with cRGD peptides, enabling a multistage mechanism of "tumor-specific recognition-nuclear targeting-stimuli-responsive release." Upon near-infrared (NIR) irradiation, the platform enhances DNA damage and suppresses the PI3K-AKT signaling pathway, thereby promoting apoptosis and inhibiting epithelial-mesenchymal transition (EMT). Both in vitro and in vivo studies demonstrated that TAT-mPDO@cRGD-M exhibited potent antitumor efficacy in cisplatin-resistant osteosarcoma models and maintained strong therapeutic activity under low-power NIR irradiation without causing damage to normal tissues or skin. This work presents a highly specific and biocompatible nanotherapeutic strategy that offers new insights and potential clinical applications for overcoming chemoresistance in osteosarcoma.