Song Dongjian, Liu Qiuliang, Zhang Da, Yan Zechen, Su Meng, Zhang Qian, Zhang Hui, Shi Longyan, Fan Yingzhong, Yang Heying
Department of Pediatric Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, People's Republic of China.
Institute of Molecular Cancer Surgery, Zhengzhou University, Henan Province Engineering Research Center, Construction East Road No.1, Erqi District, Zhengzhou, 450052, Henan, People's Republic of China.
J Transl Med. 2025 Jul 17;23(1):804. doi: 10.1186/s12967-025-06735-5.
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.
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.
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.
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.
多柔比星（Dox）耐药性仍是骨肉瘤（OS）治疗中的一项重大挑战，限制了其治疗效果并导致临床预后不佳。本研究旨在探讨使用iRGD修饰的仿生纳米颗粒（NPs）靶向递送METTL3特异性抑制剂，通过调节MCAM的m6A修饰来解决Dox耐药问题。
通过将OS细胞膜与脂质纳米颗粒融合制备仿生纳米颗粒，随后进行iRGD肽修饰以增强肿瘤靶向能力。这些纳米颗粒负载了METTL3抑制剂STM2457，并对其稳定性、药物包封效率以及对耐Dox的OS细胞的细胞摄取进行了表征。实施功能测定以检查它们对体外细胞生物学功能的影响。利用小鼠异种移植模型监测肿瘤进展和转移行为，进一步验证治疗效果。
iRGD修饰的纳米颗粒表现出优异的稳定性、高药物包封效率，并在体外显著提高了细胞摄取。METTL3抑制降低了MCAM的m6A修饰，导致耐Dox的OS细胞增殖和侵袭减少。在体内，Dox与负载METTL3的纳米颗粒联合使用显著抑制了小鼠模型中的肿瘤生长和肺转移。
iRGD修饰的仿生纳米颗粒通过靶向METTL3-MCAM轴为克服OS中的Dox耐药性提供了一种有前景的方法。该策略可能改善治疗结果，并在耐药癌症的临床应用中具有潜力。
