| Summary: | Molin Li,1,2,* Yufei Ma,3,* Hui Yao,1 Hao Jia,1 Yalan Wang,2,* Xuefeng Tang1,* 1Department of Pathology, Chongqing General Hospital, Chongqing University, Chongqing, 401147, People’s Republic of China; 2Department of Pathology, College of Basic Medicine, Chongqing Medical University, Chongqing, 400016, People’s Republic of China; 3Research Center of Stem Cells and Ageing, Chongqing Institute of Green and Intelligent Technology, Chinese Academy of Sciences, Chongqing, 400714, People’s Republic of China*These authors contributed equally to this workCorrespondence: Yalan Wang, Department of Pathology, College of Basic Medicine, Chongqing Medical University, Chongqing, 400016, People’s Republic of China, Email wangyalan0505@163.com Xuefeng Tang, Department of Pathology, Chongqing General Hospital, Chongqing University, Chongqing, 401147, People’s Republic of China, Email txfaaty@163.comPurpose: Osteosarcoma poses significant clinical challenges due to its high recurrence, metastatic potential, and poor prognosis. Celastrol (CLT), known for its antitumor, immunomodulatory, and osteogenic regulatory properties, has garnered substantial interest. Developing a targeted CLT delivery system is critical to enable precise drug release, integrate photothermal therapy, remodel the tumor microenvironment, and improve post-surgical treatment and repair in osteosarcoma.Methods: Using emulsion-induced interface assembly, we synthesized mesoporous polydopamine-polyethylene glycol (MPDA-PEG) nanospheres and loaded them with celastrol to fabricate the targeted system MPDA-PEG-CLT. We characterized the nanospheres’ physicochemical properties and evaluated MPDA-PEG-CLT’s efficacy in synergistic drug-photothermal therapy for osteosarcoma through in vitro and in vivo experiments.Results: MPDA-PEG-CLT achieved a drug loading capacity of ~14% and a photothermal conversion efficiency of 37.6% under 808 nm NIR irradiation, which enhanced celastrol release. The system induced osteosarcoma cell apoptosis, promoted bone marrow mesenchymal stem cell (BMSC) differentiation, and ameliorated the lesion microenvironment, resulting in efficient tumor ablation in mice.Conclusion: MPDA-PEG-CLT significantly enhances celastrol’s targeted delivery efficiency, promotes mitochondrial apoptosis in osteosarcoma cells, synergizes with photothermal therapy to eradicate tumors, and improves the bone tissue microenvironment in lesions. This system offers a promising strategy for post-surgical osteosarcoma treatment and repair. Keywords: photothermal therapy, mesoporous polydopamine, celastrol, mitochondrial apoptosis
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