Engineering exosomes-mediated RNA delivery regulates bone homeostasis and alleviates osteoporosis.
- 1Department of Orthopedics, The Affiliated Hospital, Southwest Medical University, Luzhou, Sichuan, 646000, China.
- 2Sichuan Provincial Laboratory of Orthopaedic Engineering, Southwest Medical University, Luzhou, Sichuan, 646000, China.
- 3Stem Cell Immunity and Regeneration Key Laboratory of Luzhou, The Affiliated Hospital, Southwest Medical University, Luzhou, Sichuan, 646000, China.
Abstract
Osteoporosis is characterized by dysregulated bone remodeling driven by excessive osteoclast-mediated bone resorption and insufficient osteoblast-mediated bone formation, often exacerbated by chronic inflammation and oxidative stress. Current pharmacological therapies remain limited by suboptimal efficacy and adverse effects, highlighting the need for alternative strategies that restore bone homeostasis. Here, we developed a bone-targeted, multifunctional exosome-based therapeutic platform by engineering M2 macrophage-derived exosomes co-loaded with platinum nanoparticles (Pt NPs) and a miR-196b inhibitor (BT-Exo-Pt-miR-196 inhibitor). The engineered exosomes exhibited preserved structural integrity, favorable biocompatibility, efficient bone-targeting capability, and excellent in vivo biosafety. Pt NPs endowed the system with robust reactive oxygen species (ROS)-scavenging activity, while M2-derived exosomes and miR-196b inhibition synergistically attenuated inflammatory cytokine expression. In vitro, BT-Exo-Pt-miR-196 inhibitor markedly enhanced osteogenic differentiation, extracellular matrix maturation, and mineralization through coordinated upregulation of osteogenic transcription factors and matrix proteins. Concurrently, osteoclastogenesis was significantly suppressed, as evidenced by reduced TRAP-positive multinucleated cells, impaired actin ring formation, and downregulation of NFATc1 and downstream osteoclast-associated markers. In an ovariectomy-induced osteoporosis mouse model, bone-targeted delivery of BT-Exo-Pt-miR-196 inhibitor effectively preserved trabecular bone microarchitecture, enhanced osteogenic activity, reduced osteoclast function, and alleviated bone loss without inducing systemic toxicity. Collectively, this study demonstrates that bone-targeted M2 macrophage-derived exosomes delivering a miR-196b inhibitor represent a promising immunomodulatory and gene-regulatory nanotherapeutic strategy for restoring bone homeostasis and treating osteoporosis.
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BibTeX
@article{du2026engineering,
title = {{Engineering exosomes-mediated RNA delivery regulates bone homeostasis and alleviates osteoporosis.}},
author = {Yimin Du and Yue Zhang and Zi Wang and Hao Jiang and Lingzhi Li and Xu Liu and Peng Zhou and Xiaoyu Huang and Juncai Liu and Zhong Li and Zheng Li},
journal = {Materials today. Bio},
year = {2026},
month = oct,
doi = {10.1016/j.mtbio.2026.103758},
url = {https://europepmc.org/article/MED/42927301},
note = {CC BY-NC},
}
RIS
TY - JOUR
TI - Engineering exosomes-mediated RNA delivery regulates bone homeostasis and alleviates osteoporosis.
AU - Yimin Du
AU - Yue Zhang
AU - Zi Wang
AU - Hao Jiang
AU - Lingzhi Li
AU - Xu Liu
AU - Peng Zhou
AU - Xiaoyu Huang
AU - Juncai Liu
AU - Zhong Li
AU - Zheng Li
PY - 2026
DA - 2026/10/17
JO - Materials today. Bio
DO - 10.1016/j.mtbio.2026.103758
UR - https://europepmc.org/article/MED/42927301
AB - Osteoporosis is characterized by dysregulated bone remodeling driven by excessive osteoclast-mediated bone resorption and insufficient osteoblast-mediated bone formation, often exacerbated by chronic inflammation and oxidative stress. Current pharmacological therapies remain limited by suboptimal efficacy and adverse effects, highlighting the need for alternative strategies that restore bone homeostasis. Here, we developed a bone-targeted, multifunctional exosome-based therapeutic platform by engineering M2 macrophage-derived exosomes co-loaded with platinum nanoparticles (Pt NPs) and a miR-196b inhibitor (BT-Exo-Pt-miR-196 inhibitor). The engineered exosomes exhibited preserved structural integrity, favorable biocompatibility, efficient bone-targeting capability, and excellent in vivo biosafety. Pt NPs endowed the system with robust reactive oxygen species (ROS)-scavenging activity, while M2-derived exosomes and miR-196b inhibition synergistically attenuated inflammatory cytokine expression. In vitro, BT-Exo-Pt-miR-196 inhibitor markedly enhanced osteogenic differentiation, extracellular matrix maturation, and mineralization through coordinated upregulation of osteogenic transcription factors and matrix proteins. Concurrently, osteoclastogenesis was significantly suppressed, as evidenced by reduced TRAP-positive multinucleated cells, impaired actin ring formation, and downregulation of NFATc1 and downstream osteoclast-associated markers. In an ovariectomy-induced osteoporosis mouse model, bone-targeted delivery of BT-Exo-Pt-miR-196 inhibitor effectively preserved trabecular bone microarchitecture, enhanced osteogenic activity, reduced osteoclast function, and alleviated bone loss without inducing systemic toxicity. Collectively, this study demonstrates that bone-targeted M2 macrophage-derived exosomes delivering a miR-196b inhibitor represent a promising immunomodulatory and gene-regulatory nanotherapeutic strategy for restoring bone homeostasis and treating osteoporosis.
SN - 2590-0064
ER -