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

被引：0

作者：

Zhan, Jingdi ^{[1
,2
]}

Zou, Jing ^{[1
,2
]}

Pang, Qiming ^{[1
,2
]}

Chen, Zhuolin ^{[1
,2
]}

Liu, Junyan ^{[1
,2
]}

Liu, Senrui ^{[1
,2
]}

Du, Chengcheng ^{[1
,2
]}

Liu, Jiacheng ^{[1
,2
]}

Zhao, Weikang ^{[1
,2
]}

Dong, Lili ^{[1
,2
]}

Huang, Wei ^{[1
,2
]}

机构：

[1] Chongqing Med Univ, Affiliated Hosp 1, Dept Orthoped, Chongqing, Peoples R China

[2] Chongqing Med Univ, Affiliated Hosp 1, Chongqing Municipal Hlth Commiss Key Lab Musculosk, Chongqing, Peoples R China

来源：

JOURNAL OF NANOBIOTECHNOLOGY | 2025年 / 23卷 / 01期

关键词：

MSCs-derived extracellular vesicles; Engineered; Macrophages; Mitochondria metabolism; mt-ND3; Osteoarthritis; MESENCHYMAL STEM-CELLS; ACTIVATED MACROPHAGES; OSTEOARTHRITIS; MITOCHONDRIA; INNATE;

D O I：

10.1186/s12951-025-03216-1

中图分类号：

Q81 [生物工程学（生物技术）]; Q93 [微生物学];

学科分类号：

071005 ; 0836 ; 090102 ; 100705 ;

摘要：

BackgroundOsteoarthritis (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.MethodsInspired 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-gamma, IL-6, and TNF-alpha), 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.ResultsiEVs, 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.ConclusionThis 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.

引用

页数：24