Nrf2 pathway activation with natural plant-derived exosome-like nanovesicle/hydrogel preparations for oxidative stress modulation in inflammation related diseases

Plant-derived exosome-like nanovesicles (PDENs) currently have significant therapeutic value in the field of disease treatment and sub-health, but the lack of suitable formulation forms further limits their clinical application. Here, we propose a novel concept of a natural plant-derived exosome-like nanovesicle-hydrogel formulation, where exosome-like nanovesicles are isolated from the outer rind of Aloe as a therapeutic component, and the inner pulp of aloe is ultrasonically crushed and concentrated to form a hydrogel matrix. The two components are then mixed to form a formulation. We found that this natural plant-derived hydrogel formulation was biocompatible and exhibited minimal immunogenicity in vivo after topical application. Further release of exosome-like nanovesicles from the hydrogel could enhance the anti-oxidant enzyme defense system in the skin via the Nrf2/HO-1 pathway, and effectively modulate the balance between oxidative and anti-oxidative states towards a more favorable physiological equilibrium in mice with atopic dermatitis (AD) lesions or diabetic wounds. Meanwhile, due to the good moisturizing property of aloe hydrogel itself, it could accelerate the repairment of natural barrier functions in inflammatory skin lesions and wound sites. Overall, this formulation is expected to be a potential and effective strategy for treating AD and diabetic wounds, and provides novel insights into the rational design of exosome-like nanovesicle formulations based on natural plant-derived components.