Antioxidant‐Engineered Milk‐Derived Extracellular Vesicles for Accelerating Wound Healing via Regulation of the PI3K‐AKT Signaling Pathway

Abstract

Inspired by the experience of relieving inflammation in infants with milk, we have developed antioxidant‐engineered milk‐derived extracellular vesicles (MEVs) to evaluate their potential for accelerating wound healing. In this work, we engineered MEVs with polydopamines (PDA) using the co‐extrusion method. Subsequently, we incorporated them into a Schiff‐based crosslink hydrogel, forming a skin dosage form that could facilitate the wound healing process. The antioxidant properties of PDA assist in the anti‐inflammatory function of engineered MEVs, while the gel provides better skin residency. The PDA@MEVs+GEL formulation exhibited excellent biocompatibility, pro‐angiogenic capacity, and antioxidant ability in vitro. Furthermore, in vivo, experiments demonstrated its efficacy in wound repair and inflammation inhibition. Mechanistically, PDA@MEVs+GEL simultaneously promoted the growth, migration, and anti‐inflammation of 3T3 cells by activating PI3K‐AKT pathway. Moreover, PDA@MEVs+GEL exhibited enhanced functionality in promoting wound healing in vivo, attributed to its ability to inhibit inflammation, stimulate angiogenesis, and promote collagen synthesis. In conclusion, this study delves into the mechanism of MEVs and underscores the improved efficacy of engineered extracellular vesicles. Additionally, the feasibility and prospect of engineered MEVs in treating skin wounds were verified, suggesting that antioxidant‐engineered MEVs could be a promising therapeutic agent for wound healing applications.This article is protected by copyright. All rights reserved

Therapeutic Potential of Bovine Milk-Derived Extracellular Vesicles

“…On the other hand, the precise mechanism used by MEVs to penetrate the epidermis barrier is still to be elucidated. In addition to those direct effects, the engineering of MEVs with polydopamine nanoparticles or hydrogels has been shown to increase the wound healing process by facilitating both their localized retention and slow release, boosting PI3-AKT-mediated angiogenic effects similar to what was previously reported for mesenchymal stem cell (MSC)-derived EVs [61]. Interestingly, bovine MEVs engineered with miR-31-5p and siRNA-KEAP1 accelerated healing effects in diabetes-dependent wounds and ulcers [62,63].…”

Bioactive microgel-coated electrospun membrane with cell-instructive interfaces and topology for abdominal wall defect repair

“…It has been reported previously that the catechol structure contained in PDA can effectively scavenge a variety of reactive oxygen species, such as hydrogen peroxide and hydroxyl radicals, and attenuate the inflammatory response at the wound site. 54,55 Moreover, the microgel coating on the PLCL membrane could provide a cell-instructive surface for cell proliferation and differentiation, which effectively accelerated tissue regeneration and also contributed to reducing the inflammation response.…”

Human Breast Milk EVs Mitigate Endothelial Dysfunction: Preliminary Study

“…Milk EVs alleviated cardiac fibrosis and enhanced cardiac function by enhancing angiogenesis. O Other studies have examined engineered milk EVs aimed at augmenting their wound-healing effectiveness, either by integrating a hydrogel material or by encapsulating potential therapeutics such as miRs 23-25 . However, the comprehensive content of milk EVs remains incompletely understood, highlighting the necessity for additional research to harness milk EVs for therapeutic purposes or as carriers for therapeutics.…”