Enhancing doxorubicin sensitivity in osteosarcoma via iRGD-modified biomimetic nanoparticles targeting MCAM m6A modification.

BACKGROUND: Doxorubicin (Dox) resistance remains a significant challenge in osteosarcoma (OS) treatment, limiting its therapeutic efficacy and contributing to poor clinical outcomes. This study aims to investigate the use of iRGD-modified biomimetic nanoparticles (NPs) for the targeted delivery of METTL3-specific inhibitors, addressing Dox resistance by regulating the m6A modification of MCAM. METHODS: Biomimetic NPs were fabricated by fusing OS cell membranes with lipid NPs, followed by iRGD peptide modification to enhance tumor targeting capability. These NPs were loaded with the METTL3 inhibitor STM2457 and characterized for stability, drug encapsulation efficiency, and cellular uptake by Dox-resistant OS cells. Functional assays were implemented to examine their impact on cell biological functions in vitro. Therapeutic efficacy was further validated utilizing a mouse xenograft model to monitor tumor progression and metastatic behavior. RESULTS: The iRGD-modified NPs exhibited excellent stability, high drug encapsulation efficiency, and significantly improved cellular uptake in vitro. METTL3 inhibition reduced MCAM m6A modification, leading to decreased proliferation and invasion of Dox-resistant OS cells. In vivo, the combination of Dox and METTL3-loaded NPs significantly inhibited tumor growth and lung metastasis in the mouse model. CONCLUSIONS: iRGD-modified biomimetic NPs offer a promising approach to overcoming Dox resistance in OS by targeting the METTL3-MCAM axis. This strategy may improve therapeutic outcomes and holds potential for clinical application in resistant cancers.