School of Biomedical Sciences and Engineering, South China University of Technology, Guangzhou International Campus, Guangzhou, 511442, PR China; Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, PR China; Hubei Province Key Laboratory of Oral and Maxillofacial Development and Regeneration, Wuhan, 430022, PR China.
Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, PR China; Hubei Province Key Laboratory of Oral and Maxillofacial Development and Regeneration, Wuhan, 430022, PR China.
Biomaterials. 2025 Jan;312:122714. doi: 10.1016/j.biomaterials.2024.122714. Epub 2024 Jul 27.
Osteosarcoma, a malignant bone tumor often characterized by high hedgehog signaling activity, residual tumor cells, and substantial bone defects, poses significant challenges to both treatment response and postsurgical recovery. Here, we developed a nanocomposite hydrogel for the sustained co-delivery of bioactive magnesium ions, anti-PD-L1 antibody (αPD-L1), and hedgehog pathway antagonist vismodegib, to eradicate residual tumor cells while promoting bone regeneration post-surgery. In a mouse model of tibia osteosarcoma, this hydrogel-mediated combination therapy led to remarkable tumor growth inhibition and hence increased animal survival by enhancing the activity of tumor-suppressed CD8 T cells. Meanwhile, the implanted hydrogel improved the microenvironment of osteogenesis through long-term sustained release of Mg, facilitating bone defect repair by upregulating the expression of osteogenic genes. After 21 days, the expression levels of ALP, COL1, RUNX2, and BGLAP in the Vis-αPD-L1-Gel group were approximately 4.1, 5.1, 5.5, and 3.4 times higher than those of the control, respectively. We believe that this hydrogel-based combination therapy offers a potentially valuable strategy for treating osteosarcoma and addressing the tumor-related complex bone diseases.
骨肉瘤是一种恶性骨肿瘤，其特征通常为高 hedgehog 信号活性、残留肿瘤细胞和大量骨缺损，这对治疗反应和术后恢复都构成了重大挑战。在这里，我们开发了一种纳米复合水凝胶，用于持续共递送生物活性镁离子、抗 PD-L1 抗体（αPD-L1）和 hedgehog 通路拮抗剂 vismodegib，以消灭残留的肿瘤细胞，同时促进术后骨再生。在胫骨骨肉瘤的小鼠模型中，这种水凝胶介导的联合治疗通过增强受抑 CD8 T 细胞的活性，显著抑制肿瘤生长，从而提高动物存活率。同时，植入的水凝胶通过长期持续释放 Mg 来改善成骨微环境，通过上调成骨基因的表达来促进骨缺损修复。21 天后，Vis-αPD-L1-Gel 组的 ALP、COL1、RUNX2 和 BGLAP 的表达水平分别约为对照组的 4.1、5.1、5.5 和 3.4 倍。我们相信，这种基于水凝胶的联合治疗为治疗骨肉瘤和解决与肿瘤相关的复杂骨病提供了一种有价值的策略。
