A biomimetic senotherapy replenishing MAT2A promotes wound regeneration in preclinical models

Dongming Lv, Lei Ren, Zirui Zhao, Yanchao Rong, Miao Chen, Hao Yang, Rong Yin, Ruixi Zeng, Hua Chao, Xiaohui Li, Zhongye Xu, Zhicheng Hu, Xiaoling Cao, Wuguo Deng (), Qing Tang () and Bing Tang ()
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Dongming Lv: First Affiliated Hospital of Sun Yat-sen University, Division of Plastic and Reconstructive Surgery
Lei Ren: First Affiliated Hospital of Sun Yat-sen University, Division of Plastic and Reconstructive Surgery
Zirui Zhao: First Affiliated Hospital of Sun Yat-sen University, Division of Plastic and Reconstructive Surgery
Yanchao Rong: First Affiliated Hospital of Sun Yat-sen University, Division of Plastic and Reconstructive Surgery
Miao Chen: Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer
Hao Yang: the First Affiliated Hospital of Sun yat-sen University, Department of Burns, Wound Repair and Reconstruction
Rong Yin: the First Affiliated Hospital of Sun yat-SEN University, Department of Dermatology
Ruixi Zeng: First Affiliated Hospital of Sun Yat-sen University, Division of Plastic and Reconstructive Surgery
Hua Chao: First Affiliated Hospital of Sun Yat-sen University, Division of Plastic and Reconstructive Surgery
Xiaohui Li: the First Affiliated Hospital of Sun yat-sen University, Department of Burns, Wound Repair and Reconstruction
Zhongye Xu: the First Affiliated Hospital of Sun yat-sen University, Department of Burns, Wound Repair and Reconstruction
Zhicheng Hu: the First Affiliated Hospital of Sun yat-sen University, Department of Burns, Wound Repair and Reconstruction
Xiaoling Cao: First Affiliated Hospital of Sun Yat-sen University, Division of Plastic and Reconstructive Surgery
Wuguo Deng: Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer
Qing Tang: First Affiliated Hospital of Sun Yat-sen University, Division of Plastic and Reconstructive Surgery
Bing Tang: First Affiliated Hospital of Sun Yat-sen University, Division of Plastic and Reconstructive Surgery

Nature Communications, 2025, vol. 16, issue 1, 1-21

Abstract: Abstract Timely infiltration and effective turnover of macrophages after trauma are essential for wound regeneration. In pathological conditions, such as diabetic wounds, how disturbances in cellular collaboration leads to persistent inflammatory infiltration remains unclear. Herein, we identify that the expression of methionine adenosyltransferase 2 A (MAT2A), which is downregulated in pericytes, is negatively correlated with inflammatory macrophage infiltration in diabetic wounds. Cspg4-CreERT2/+; Mat2aflox/flox female mouse model and single-cell sequencing of its wound tissue reveal that TAM induced-Mat2a deficiency in pericytes induces cell senescence and further drives the inflammatory trained immunity of infiltrating macrophages through senescence-associated secretory phenotype factors and cellular mitochondrial transfer. Mechanistically, MAT2A downregulation in pericyte reduces the recruitment of the deubiquitinase OTUB1 to HMGCS1 and thus reduces HMGCS1 expression level, thereby interfering with coenzyme Q synthesis, affecting mitochondrial function, and inducing cell senescence. We then coat self-amplifying RNA-loaded nanoparticles with pericyte membrane to restore stable MAT2A expression in senescent pericytes, effectively alleviating the persistent inflammatory macrophage infiltration and promoting wound regeneration. Our results reveal MAT2A as a potential therapeutic target in chronic inflammatory wounds and suggest a targeting senotherapy based on a biomimetic strategy.

Date: 2025
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DOI: 10.1038/s41467-025-65659-2

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