MSCs-EVs harboring OA immune memory reprogram macrophage phenotype via modulation of the mt-ND3/NADH-CoQ axis for OA treatment

  • J Nanobiotechnology. 2025 Feb 25;23(1):140. doi: 10.1186/s12951-025-03216-1.
Jingdi Zhan  1  2 ,  Jing Zou  1  2 ,  Qiming Pang  1  2 ,  Zhuolin Chen  1  2 ,  Junyan Liu  1  2 ,  Senrui Liu  1  2 ,  Chengcheng Du  1  2 ,  Jiacheng Liu  1  2 ,  Weikang Zhao  3  4 ,  Lili Dong  5  6 ,  Wei Huang  7  8
Affiliations
  • 1. Department of Orthopedics, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.
  • 2. Chongqing Municipal Health Commission Key Laboratory of Musculoskeletal Regeneration and Translational Medicine, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.
  • 3. Department of Orthopedics, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China. [email protected].
  • 4. Chongqing Municipal Health Commission Key Laboratory of Musculoskeletal Regeneration and Translational Medicine, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China. [email protected].
  • 5. Department of Orthopedics, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China. [email protected].
  • 6. Chongqing Municipal Health Commission Key Laboratory of Musculoskeletal Regeneration and Translational Medicine, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China. [email protected].
  • 7. Department of Orthopedics, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China. [email protected].
  • 8. Chongqing Municipal Health Commission Key Laboratory of Musculoskeletal Regeneration and Translational Medicine, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China. [email protected].
PMID: 40001168 DOI: 10.1186/s12951-025-03216-1
Abstract

Background: Osteoarthritis (OA) is a prevalent degenerative joint disease and current therapies are insufficient to halt its progression. Mesenchymal stem cells-derived extracellular vesicles (MSCs-EVs) offer promising therapeutic potential for OA treatment, and their efficacy can be enhanced through strategic engineering approaches.

Methods: Inspired by the immune memory of the adaptive immune system, we developed an engineered strategy to impart OA-specific immune memory to MSCs-EVs. Using Luminex technology, inflammatory factors (IFN-γ, IL-6, and TNF-α), which mimic the OA inflammatory microenvironment, were identified and used to prime MSCs, generating immune memory-bearing MSCs-EVs (iEVs). Proteomic analysis and complementary experiments were conducted to evaluate iEVs' effects on macrophage phenotypic reprogramming.

Results: iEVs, particularly IL-6-EV, exhibited potent immunoregulatory functions along with the ability to modulate Mitochondrial Metabolism. Both in vitro and in vivo, IL-6-EV significantly reprogrammed macrophages towards the M2 subtype, effectively suppressing articular inflammation and OA progression. Mechanistic studies revealed that IL-6-EV facilitated M2 polarization by regulating mitochondrial Oxidative Phosphorylation via the mt-ND3/NADH-CoQ axis.

Conclusion: This study introduces a strategy to enhance MSCs-EVs' therapeutic efficacy in OA. Multi-omics analysis and biological validation demonstrate its potential, providing new insights for MSCs-EVs' future application in OA and Other clinical conditions.

Keywords
Engineered; MSCs-derived extracellular vesicles; Macrophages; Mitochondria metabolism; Osteoarthritis; mt-ND3.
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