Cascade-Targeting Nanoparticles for Reversing Chemoresistance in Osteosarcoma

Abstract Osteosarcoma (OS) remains the most prevalent primary malignant bone tumor in adolescents, with chemotherapy resistance significantly limiting the efficacy of current treatments. To address the challenges of chemoresistance driven by DNA repair mechanisms and drug efflux, we developed a biomimetic cascade-targeting drug delivery system, TAT-mPDO@cRGD-M. This system combines a polydopamine (mPDA) core with strong photothermal and drug-loading capacities, enabling the co-delivery of cisplatin (CDDP) and olaparib (OLA). Surface functionalization with the nuclear localization peptide TAT and cloaking with osteosarcoma cell membranes modified with cRGD peptides allows for selective tumor recognition, nuclear targeting, and stimuli-responsive drug release. Upon near-infrared (NIR) irradiation, the platform enhances DNA damage, suppresses the PI3K-AKT signaling pathway, and promotes apoptosis while inhibiting epithelial-mesenchymal transition (EMT). In vitro and in vivo studies demonstrated that TAT-mPDO@cRGD-M exhibits potent antitumor activity against cisplatin-resistant osteosarcoma, maintaining strong therapeutic efficacy under low-power NIR irradiation without causing significant damage to normal tissues. This study highlights a highly specific and biocompatible therapeutic approach that offers promising potential for overcoming chemotherapy resistance in osteosarcoma and advancing clinical treatment strategies. Competing Interest Statement The authors have declared no competing interest. Footnotes This revised version of the manuscript includes substantial improvements in language quality and overall presentation. The manuscript has undergone comprehensive English editing to enhance clarity, readability, and scientific expression throughout the text. The title and abstract were revised to better reflect the main findings and significance of the study. Some cell functional assay results were removed or corrected following further evaluation to ensure accuracy and rigor. Additional mechanistic experimental results were incorporated to further strengthen the study. In addition, all figures were reorganized and reformatted to improve visual consistency and data presentation, and the main findings were consolidated into six primary figures. Additional supporting data and related experimental results have been transferred to the Supplementary Materials to improve the overall structure and focus of the manuscript.