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Updated: Aug 5, 2026
Intratibial Osteosarcoma Cell Injection to Generate Orthotopic Osteosarcoma and Lung Metastasis Mouse Models
Published on: October 28, 2021
Engineering a tumor-homing ZIF-8 nanoplatform for safe and synergistic immunotherapy of osteosarcoma
Linjie Zeng1, Youyou Shao2, Zhiyi Zhou3
1Department of Orthopedic Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, PR China; Orthopedics Research Institute of Zhejiang University, Hangzhou, Zhejiang, PR China; Key Laboratory of Motor System Disease Research and Precision Therapy of Zhejiang Province, Hangzhou, Zhejiang, PR China; Clinical Research Center of Motor System Disease of Zhejiang Province, PR China; Xiamen Haicang Hospital, Xiamen, Fujian, PR China.
Abstract:
Osteosarcoma, a highly heterogeneous tumor with an immunosuppressive microenvironment, remains therapeutically refractory because of the dominance of M2-polarized macrophages and myeloid-derived suppressor cells (MDSCs) and the lack of effective immune activation. In this study, we developed a tumor-targeted, pH-responsive nanoplatform (OTP@ZIF-8) based on a ZIF-8 scaffold co-loaded with an anti-CD47 monoclonal antibody (mAb) and hydralazine and functionalized with a phage display-identified osteosarcoma-homing peptide. Hydralazine suppressed MDSC-mediated immunosuppression by inhibiting methylglyoxal biosynthesis, while anti-CD47 mAb enhanced macrophage phagocytosis by blocking the "don't-eat-me" signal. Peptide-guided targeting combined with stimuli-responsive release enabled selective intratumoral accumulation, reduced systemic toxicity, and eliminated anti-CD47-induced hemolysis. In vitro and in vivo, OTP@ZIF-8 synergistically inhibited tumor growth by remodeling the immunosuppressive microenvironment, decreasing M2-polarized macrophages and MDSCs while promoting phagocytosis and T-cell activation. This study offers a rational and multifunctional strategy for precision immunotherapy against highly heterogeneous tumors.
Insights
This study presents a novel nanoplatform for osteosarcoma immunotherapy. It effectively targets tumors, reduces immunosuppression, and enhances immune cell activity for improved treatment outcomes.
Area of Science:
- Oncology
- Immunotherapy
- Nanomedicine
Background:
- Osteosarcoma is a heterogeneous tumor with an immunosuppressive microenvironment, hindering effective treatment.
- Dominance of M2 macrophages and myeloid-derived suppressor cells (MDSCs) contributes to therapeutic refractoriness.
- Lack of effective immune activation strategies limits current osteosarcoma therapies.
Purpose of the Study:
- To develop a tumor-targeted, pH-responsive nanoplatform for osteosarcoma immunotherapy.
- To co-load hydralazine and anti-CD47 monoclonal antibody (mAb) onto the nanoplatform for synergistic effects.
- To functionalize the nanoplatform with an osteosarcoma-homing peptide for targeted delivery.
Main Methods:
- Development of OTP@ZIF-8, a ZIF-8 based nanoplatform.
- Co-loading hydralazine to suppress MDSC-mediated immunosuppression and anti-CD47 mAb to enhance macrophage phagocytosis.
- Functionalization with a phage display-identified osteosarcoma-homing peptide for targeted delivery and stimuli-responsive release.
Main Results:
- OTP@ZIF-8 demonstrated selective intratumoral accumulation, reducing systemic toxicity and anti-CD47-induced hemolysis.
- The nanoplatform synergistically inhibited tumor growth in vitro and in vivo.
- OTP@ZIF-8 remodeled the immunosuppressive microenvironment by decreasing M2 macrophages and MDSCs, promoting phagocytosis and T-cell activation.
Conclusions:
- The developed nanoplatform offers a rational and multifunctional strategy for precision immunotherapy against osteosarcoma.
- Targeted delivery and stimuli-responsive release are key to reducing toxicity and enhancing efficacy.
- This approach holds promise for overcoming therapeutic resistance in highly heterogeneous tumors.
