Reprogramming the Wound Microenvironment: Identity Remodeling Strategies for Fibroblasts, Keratinocytes, and Macrophages

This document discusses a novel approach to treating chronic non-healing wounds by reprogramming the identity of wound-repair cells, which traditional therapies struggle to address. The authors propose a "four-dimensional technology toolbox" that includes transcription factor-mediated, small-molecule-induced, epigenetic and metabolic regulation, and nanomaterial-assisted delivery. This toolbox is used to reprogram fibroblasts, keratinocytes, and macrophages to more regenerative and reparative phenotypes. The paper critically evaluates the molecular mechanisms and clinical translation challenges, such as safety and precision, and highlights emerging technologies like AI-driven materials and trained immunity. The work aims to shift wound treatment towards a precision systems-engineering paradigm, offering a comprehensive framework for precision reprogramming therapy.