Probiotics and Extracellular Vesicles as Redox Modulators in Wound Healing: From Microbial Therapeutics to Engineered...

Chronic wounds are characterized by prolonged inflammation, excess oxidative stress, unregulated angiogenesis, and faulty tissue regeneration that are associated with slow wound healing and poor clinical outcomes. Reactive oxygen species (ROS) signaling deregulation is involved in the pathway of chronic wound pathophysiology, altering redox balance, augmenting the inflammatory response, and inhibiting the cellular response. In this review, a structured literature search and evidence-screening process was used to synthesize evidence on probiotics, EVs, and engineered EVs derived from probiotics in the context of wound healing. Studies suggest that EVs from probiotics may impact redox-sensitive processes of wound healing, including changes associated with Nrf2/HO-1, NF-κB signaling, modulation of mitochondrial ROS, macrophage polarization, and repair of the epithelial barrier. Many of these mechanistic links are derived from pathway-based markers or indirect experiments, however, and will need further mechanistic validation. Probiotic-EVs may offer potential advantages over traditional antioxidant delivery and mammalian-EV systems, including being cell-free, compatible with the microbiome, and easy to engineer. Recent progress in synthetic biology, cargo loading, biomaterial-assisted delivery systems, and ROS-responsive platforms may enable engineered probiotic-EVs to serve as programmable redox nanotherapies. However, major issues regarding EV standardization, biosafety, biodistribution, pharmacokinetics, and clinical validation remain unresolved. Importantly, the evidence for the application of probiotic-derived EVs to wound healing is predominantly preclinical, and there is a lack of direct clinical evidence to date. Collectively, EVs secreted from probiotics might hold potential for chronic wound care and redox-oriented regenerative medicine as a therapeutic platform.