Multimodal hydrogel modulation of extracellular vesicle cargo to arrest post-traumatic osteoarthritis in murine models
8 affiliations
- 1Department of Orthopedics, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, China
- 2Department of Orthopedics, Shanghai Tenth People’s Hospital, School of Medicine, Tongji University, Shanghai, China
- 3Department of Orthopedics, State Key Laboratory of Immune Response and Immunotherapy, Centre for Leading Medicine and Advanced Technologies of IHM, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
- 4Department of Orthopedics, The First Affiliated Hospital of Anhui University of Science and Technology, Huainan, China
- 5Department of Sports Medicine, State Key Laboratory of Frigid Zone Cardiovascular Diseases, The Guangzhou Key Laboratory of Precision Orthopedics and Regenerative Medicine, Guangdong Provincial Key Laboratory of Speed Capability, The First Affiliated Hospital, Jinan University, Guangzhou, China
- 6Department of Orthopedics, The Second Affiliated Hospital of Anhui University of Chinese Medicine, Hefei, China
- 7Department of Geriatric, Shanghai General Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
- 8Department of Orthopedics, Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai Jiao Tong University, Shanghai, China
Abstract
Effective prophylactic interventions for exercise-induced joint damage and preclinical osteoarthritis remain elusive, as abnormal mechanical loading drives pathology through a dual pyroptotic loop between chondrocytes and macrophages. We present PMUC, a mechano-responsive lubricating hydrogel engineered for graded joint protection and repair. Mimicking native lubrication, intra-articular PMUC forms a persistent hydration layer that dissipates mechanical stress. Under pathological load, stress-induced reactive oxygen species trigger mannose and nanocomplex release. This cascade activates the hexosamine biosynthetic pathway, suppressing Caspase-3/GSDME-mediated chondrocyte pyroptosis while concurrently reprogramming macrophage-derived extracellular vesicles. Enriched with XIAP and OTULIN proteins, these in situ-generated extracellular vesicles act as intercellular messengers that disrupt the inflammatory cycle and facilitate matrix regeneration. In preclinical rat models of high-load exercise and post-traumatic OA, PMUC prevents cartilage erosion and achieves full regeneration with restored locomotion within eight weeks. Here we show that PMUC integrates adaptive lubrication with stress-triggered immune-metabolic modulation, offering a first‑in‑class strategy to protect joints and alleviate early OA.
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BibTeX
@article{zhang2026multimodal,
title = {{Multimodal hydrogel modulation of extracellular vesicle cargo to arrest post-traumatic osteoarthritis in murine models}},
author = {Xudong Zhang and Wei Zhu and Huajun Wang and Yingjie Wang and Ziheng Bu and Wei Liu and Junchao Huang and Jiawei Mei and Quan Liu and Jiachang Hong and Jianing Yu and JinXi An and Sudan Xu and Chen Zhu and Wanbo Zhu and Peng Wu},
journal = {Nature Communications},
year = {2026},
month = sep,
doi = {10.1038/s41467-026-77833-1},
url = {https://doi.org/10.1038/s41467-026-77833-1},
note = {CC BY-NC-ND 4.0},
}
RIS
TY - JOUR
TI - Multimodal hydrogel modulation of extracellular vesicle cargo to arrest post-traumatic osteoarthritis in murine models
AU - Xudong Zhang
AU - Wei Zhu
AU - Huajun Wang
AU - Yingjie Wang
AU - Ziheng Bu
AU - Wei Liu
AU - Junchao Huang
AU - Jiawei Mei
AU - Quan Liu
AU - Jiachang Hong
AU - Jianing Yu
AU - JinXi An
AU - Sudan Xu
AU - Chen Zhu
AU - Wanbo Zhu
AU - Peng Wu
PY - 2026
DA - 2026/09/24
JO - Nature Communications
DO - 10.1038/s41467-026-77833-1
UR - https://doi.org/10.1038/s41467-026-77833-1
AB - Effective prophylactic interventions for exercise-induced joint damage and preclinical osteoarthritis remain elusive, as abnormal mechanical loading drives pathology through a dual pyroptotic loop between chondrocytes and macrophages. We present PMUC, a mechano-responsive lubricating hydrogel engineered for graded joint protection and repair. Mimicking native lubrication, intra-articular PMUC forms a persistent hydration layer that dissipates mechanical stress. Under pathological load, stress-induced reactive oxygen species trigger mannose and nanocomplex release. This cascade activates the hexosamine biosynthetic pathway, suppressing Caspase-3/GSDME-mediated chondrocyte pyroptosis while concurrently reprogramming macrophage-derived extracellular vesicles. Enriched with XIAP and OTULIN proteins, these in situ-generated extracellular vesicles act as intercellular messengers that disrupt the inflammatory cycle and facilitate matrix regeneration. In preclinical rat models of high-load exercise and post-traumatic OA, PMUC prevents cartilage erosion and achieves full regeneration with restored locomotion within eight weeks. Here we show that PMUC integrates adaptive lubrication with stress-triggered immune-metabolic modulation, offering a first‑in‑class strategy to protect joints and alleviate early OA.
SN - 2041-1723
ER -