Reprogramming the wound microenvironment: identity remodeling strategies for fibroblasts, keratinocytes, and...

The core pathology of chronic non-healing wounds is the dysfunction of wound-repair cells-a molecular defect that conventional passive therapies can hardly correct at its root. Cell reprogramming techniques, by actively rewriting cell identity, have therefore brought a paradigm shift to wound repair. Herein, we propose a systematic "four-dimensional technology toolbox" for wound cell reprogramming, comprising transcription factor-mediated, small-molecule-induced, epigenetic and metabolic regulation, and nanomaterial-assisted delivery. Using this toolbox as the main thread, we comprehensively integrate three core cell-identity reprogramming strategies: fibroblasts (from a profibrotic scar-forming phenotype to a pro-regenerative repair-competent phenotype), keratinocytes (restoring the endogenous regenerative capacity of keratinocytes to reconstruct the epidermal barrier), and macrophages (from a pro-inflammatory pathological state to a reparative homeostatic phenotype). Remedying the principal weaknesses of existing reviews-overemphasis on technique listing, weak mechanistic integration, and lack of translational critique-we dissect the key molecular mechanisms layer by layer and critically evaluate the core clinical-translation bottlenecks, including safety, spatiotemporal precision, and model systems. Finally, we spotlight emerging frontiers such as single-cell multi-omics navigation, AI-driven temporally programmed smart materials, and trained immunity, and discuss how they propel the field from proof-of-concept toward a precision systems-engineering paradigm of "personalized diagnosis → intelligent sequential delivery → closed-loop healing monitoring". This work not only offers a novel intervention paradigm for the core challenges of treating chronic non-healing wounds like diabetic foot ulcers, but also delivers a panoramic theoretical framework and practical guidance for precision reprogramming therapy-from fundamental mechanisms to clinical translation.