Turritopsis nutricula-Inspired Engineered Biomimetic Skin Promoting Aged Wound Repair via DAZAP1 Phase Separation-Related Mitochondrial Metabolism Reprogramming.

Aging-associated wound healing deficiency causes a variety of health complications and makes both economic and psychological burdens on patients greatly, with current therapies failing to address underlying pathophysiology and aging-related impairments. Inspired by Turritopsis nutricula, we directly fabricated biomimetic skin matrix (BSM) from human adipose tissue (AT) by decellularization, then incorporated with amino-functionalized apoptotic bodies (FABs) to construct a biomimetic skin (BSM@FABs). BSM@FABs effectively displayed high fibroblast affinity while reversing cellular senescence, accelerating migration, and stimulating neovascularization in aged wounds. Mechanistically, we identified a pioneering DAZAP1 liquid-liquid phase separation (LLPS) triggered by BSM@FABs. These biomolecular condensates in the LLPS process enhanced tricarboxylic acid (TCA) cycle flux and oxidative phosphorylation (OXPHOS), concomitant with suppressed glycolysis and reduced mitochondrial reactive oxygen species, thereby resolving aging-impaired mitochondrial dysfunction. Our work introduces a novel LLPS-targeted strategy for aged wound treatment by reprogramming mitochondrial energy metabolism.