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

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

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. weikangzhao90@hospital.cqmu.edu.cn.
  • 4 Chongqing Municipal Health Commission Key Laboratory of Musculoskeletal Regeneration and Translational Medicine, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China. weikangzhao90@hospital.cqmu.edu.cn.
  • 5 Department of Orthopedics, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China. dllbme@alu.cqu.edu.cn.
  • 6 Chongqing Municipal Health Commission Key Laboratory of Musculoskeletal Regeneration and Translational Medicine, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China. dllbme@alu.cqu.edu.cn.
  • 7 Department of Orthopedics, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China. huangwei68@263.net.
  • 8 Chongqing Municipal Health Commission Key Laboratory of Musculoskeletal Regeneration and Translational Medicine, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China. huangwei68@263.net.
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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