A biomimetic senotherapy replenishing MAT2A promotes wound regeneration in preclinical models

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-CreER^T2/+; Mat2a^flox/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.