M1 macrophage-derived fusogenic nanovesicles co-loaded with Fe3O4/IR780 suppress osteosarcoma via a sonodynamic-ferroptosis-immune triad
- 1Department of Orthopedics, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
- 2Department of Orthopedics, Huzhou Key Laboratory of Early Diagnosis and Treatment of Osteoarthritis, The First People’s Hospital of Huzhou, Huzhou, China
- 3Department of Orthopaedics, Lanzhou University Second Hospital, Lanzhou, China
Abstract
Osteosarcoma, a highly aggressive and metastatic bone malignancy, remains difficult to treat with current therapeutic modalities, leading to unsatisfactory clinical outcomes. Emerging evidence indicates that ferroptosis induction and antitumor immune activation represent promising therapeutic avenues. Herein, we engineer a biomimetic nanoplatform, termed IR780@NVEV-Fe3O4 (IFV), by fusing M1 macrophage-derived extracellular vesicles with extruded nanovesicles preloaded with Fe3O4 nanoparticles and the sonosensitizer IR780, aiming to integrate sonodynamic therapy (SDT), ferroptosis induction, and immunotherapy into a single system. The IFV nanoplatform exhibits excellent tumor-targeting capability and pronounced ultrasound responsiveness. In vitro, ultrasound-activated IFV potently induces ferroptosis in osteosarcoma cells, as evidenced by enhanced lipid peroxidation, mitochondrial dysfunction, and suppression of the GPX4/xCT axis. Notably, this process concurrently triggers immunogenic cell death (ICD), thereby promoting dendritic cell maturation and macrophage polarization toward the M1 phenotype. In murine osteosarcoma models, IFV combined with ultrasound markedly inhibits subcutaneous tumor growth and pulmonary metastasis. Importantly, the combination of IFV-mediated sonodynamic therapy with anti-PD-L1 antibody elicits a robust systemic antitumor immune response, characterized by enhanced intratumoral CD8⁺ T cell infiltration, establishment of long-term immunological memory, and a substantial prolongation of host survival. Collectively, this study presents a versatile biomimetic nanoplatform that operates through a self-reinforcing “sonodynamic-ferroptosis- immune” triad, providing a promising and effective combinatorial strategy for osteosarcoma therapy.
Graphical abstract:
Supplementary Information: The online version contains supplementary material available at https://doi.org/10.1186/s12951-026-04882-5.
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BibTeX
@article{liu2026macrophagederived,
title = {{M1 macrophage-derived fusogenic nanovesicles co-loaded with Fe3O4/IR780 suppress osteosarcoma via a sonodynamic-ferroptosis-immune triad}},
author = {Qimeng Liu and Jiangyu Nan and Rong Wu and Feng Hua and Zheyu Zhang and Bin Zhang and Wenyu Wu and Yuanhan Li and Shuailong Liang and Guanzhi Liu and Yute Yang and Chihao Jin and Tianliang Ma and Yihe Hu and Jie Xie},
journal = {Journal of Nanobiotechnology},
year = {2026},
month = aug,
doi = {10.1186/s12951-026-04882-5},
url = {https://doi.org/10.1186/s12951-026-04882-5},
note = {CC BY-NC-ND 4.0},
}
RIS
TY - JOUR
TI - M1 macrophage-derived fusogenic nanovesicles co-loaded with Fe3O4/IR780 suppress osteosarcoma via a sonodynamic-ferroptosis-immune triad
AU - Qimeng Liu
AU - Jiangyu Nan
AU - Rong Wu
AU - Feng Hua
AU - Zheyu Zhang
AU - Bin Zhang
AU - Wenyu Wu
AU - Yuanhan Li
AU - Shuailong Liang
AU - Guanzhi Liu
AU - Yute Yang
AU - Chihao Jin
AU - Tianliang Ma
AU - Yihe Hu
AU - Jie Xie
PY - 2026
DA - 2026/08/08
JO - Journal of Nanobiotechnology
DO - 10.1186/s12951-026-04882-5
UR - https://doi.org/10.1186/s12951-026-04882-5
AB - Osteosarcoma, a highly aggressive and metastatic bone malignancy, remains difficult to treat with current therapeutic modalities, leading to unsatisfactory clinical outcomes. Emerging evidence indicates that ferroptosis induction and antitumor immune activation represent promising therapeutic avenues. Herein, we engineer a biomimetic nanoplatform, termed IR780@NVEV-Fe3O4 (IFV), by fusing M1 macrophage-derived extracellular vesicles with extruded nanovesicles preloaded with Fe3O4 nanoparticles and the sonosensitizer IR780, aiming to integrate sonodynamic therapy (SDT), ferroptosis induction, and immunotherapy into a single system. The IFV nanoplatform exhibits excellent tumor-targeting capability and pronounced ultrasound responsiveness. In vitro, ultrasound-activated IFV potently induces ferroptosis in osteosarcoma cells, as evidenced by enhanced lipid peroxidation, mitochondrial dysfunction, and suppression of the GPX4/xCT axis. Notably, this process concurrently triggers immunogenic cell death (ICD), thereby promoting dendritic cell maturation and macrophage polarization toward the M1 phenotype. In murine osteosarcoma models, IFV combined with ultrasound markedly inhibits subcutaneous tumor growth and pulmonary metastasis. Importantly, the combination of IFV-mediated sonodynamic therapy with anti-PD-L1 antibody elicits a robust systemic antitumor immune response, characterized by enhanced intratumoral CD8⁺ T cell infiltration, establishment of long-term immunological memory, and a substantial prolongation of host survival. Collectively, this study presents a versatile biomimetic nanoplatform that operates through a self-reinforcing “sonodynamic-ferroptosis- immune” triad, providing a promising and effective combinatorial strategy for osteosarcoma therapy. Graphical abstract: Supplementary Information: The online version contains supplementary material available at https://doi.org/10.1186/s12951-026-04882-5.
SN - 1477-3155
ER -