A review of immune regulation and novel therapeutic strategies for non-healing wound repair

Abstract

Non-healing wounds, including diabetic foot ulcers, venous ulcers, pressure injuries, and infected wounds, represent a growing global health burden with limited effective treatments. Their pathogenesis is driven by persistent dysregulation of the immune microenvironment, rather than simple failure of individual repair pathways. This review systematically examines the molecular and cellular mechanisms underlying chronic wound non-healing, with a focus on three interconnected immune pathologies: sustained M1 macrophage polarization, excessive NET formation, and imbalance between pro-inflammatory Th17 and regulatory T cells. These abnormalities are further reinforced by dysfunctional MSC activity and persistent NLRP3 inflammasome activation, creating a self-sustaining pro-inflammatory loop that blocks tissue regeneration. Based on this mechanistic framework, we review emerging therapeutic strategies designed to reprogram the wound immune microenvironment. These include temporally controlled macrophage polarization using smart biomaterials, targeted clearance or inhibition of NETs, restoration of Th17/Treg balance via epigenetic modulators or engineered exosomes, and MSC-based regenerative approaches with enhanced paracrine function. Advanced delivery systems such as stimuli-responsive hydrogels, acellular dermal matrix scaffolds, and cell-free exosome therapies are highlighted for their ability to achieve localized, on-demand immunomodulation. Finally, we critically analyze major translational barriers, including insufficient large-scale clinical validation, lack of real-time immune monitoring biomarkers, and regulatory challenges for combination products. We propose that future breakthroughs depend on establishing a human wound immune atlas, developing dynamic immune phenotyping tools, and constructing closed-loop smart dressings that integrate sensing, diagnosis, and immunomodulatory delivery. This review provides a roadmap for translating immune-centric mechanisms into next-generation precision therapies for non-healing wounds.