Nanocascade Engineering Workshop for Synergistic Microenvironment Reprogramming and EpSC Revitalization in Precise Diabetic Wound Therapy

ABSTRACT Chronic wounds are life‐threatening conditions characterized by impaired closure. Chronic inflammation and impaired regeneration and repair lead to the pathological phenotype of chronic diabetic wounds and reduce drug efficacy. In this study, we found that the poor proliferative and differentiative ability of epidermal stem cells (EpSCs) within an inflammatory microenvironment is a key factor contributing to the delayed healing of chronic diabetic wounds. To address this issue, we designed a nanocascade engineering workshop (Cu 5.4 O@LL‐37/pDNA) capable of simultaneously reshaping the inflammatory microenvironment and activating EpSC functions to promote rapid wound closure. The workshop used a core–shell structure design. The core, an ultrasmall Cu 5.4 O nanozyme, can efficiently eliminate reactive oxygen species, enhance the inflammatory response, and transform the pathological wound microenvironment into a niche facilitating regeneration. The shell is constructed through the electrostatic assembly of plasmid DNA (pDNA) and the antibacterial peptide LL‐37, enhancing gene transfection efficiency and inhibiting bacterial infection effectively. By leveraging its dual advantages in microenvironment modulation and structural design, the system substantially improves gene delivery and facilitates sustained P311 expression, thereby promoting EpSC proliferation and differentiation. This nanotherapy reshaping the microenvironment and activating EpSC function accelerates re‐epithelialization and wound closure in both diabetes and infection models. This treatment strategy is a novel approach to achieve durable and effective healing in chronic wounds.