Local Immunomodulation Using an Adhesive Hydrogel Loaded with miRNA‐Laden Nanoparticles Promotes Wound Healing

Abstract

Chronic wounds are characterized by impaired healing and uncontrolled inflammation, which compromise the protective role of the immune system and may lead to bacterial infection. Upregulation of miR‐223 microRNAs (miRNAs) shows driving of the polarization of macrophages toward the anti‐inflammatory (M2) phenotype, which could aid in the acceleration of wound healing. However, local‐targeted delivery of microRNAs is still challenging, due to their low stability. Here, adhesive hydrogels containing miR‐223 5p mimic (miR‐223*) loaded hyaluronic acid nanoparticles are developed to control tissue macrophages polarization during wound healing processes. In vitro upregulation of miR‐223* in J774A.1 macrophages demonstrates increased expression of the anti‐inflammatory gene Arg‐1 and a decrease in proinflammatory markers, including TNF‐α, IL‐1β, and IL‐6. The therapeutic potential of miR‐223* loaded adhesive hydrogels is also evaluated in vivo. The adhesive hydrogels could adhere to and cover the wounds during the healing process in an acute excisional wound model. Histological evaluation and quantitative polymerase chain reaction (qPCR) analysis show that local delivery of miR‐223* efficiently promotes the formation of uniform vascularized skin at the wound site, which is mainly due to the polarization of macrophages to the M2 phenotype. Overall, this study demonstrates the potential of nanoparticle‐laden hydrogels conveying miRNA‐223* to accelerate wound healing.

Hydrogel-Based Localized Nonviral Gene Delivery in Regenerative Medicine Approaches—An Overview

“…Yet, even though numerous studies conducted in clinically relevant animal models in vivo reinforce the potential of hydrogel-based nonviral gene delivery for the treatment of different pathologies [35,50,[56][57][58][59][60]92], there are not, to the best of our knowledge, clinical trials thus far reporting the feasibility of exploiting these adapted biomaterials to deliver nonviral vectors.…”

“…Therefore, reprogramming of macrophages toward the M2 phenotype via miRNAs has emerged as a potential strategy for the treatment of these chronic disorders. Saleh et al developed adhesive hydrogels containing miR-223 5p mimic (miR-223)-loaded HA nanoparticles to control tissue macrophages polarization during wound healing processes [60]. These adhesive systems could adhere to and cover the wounds during the healing process in an acute excisional wound model.…”

Stimuli-Responsive Hydrogels for Local Post-Surgical Drug Delivery

“…They used miR-223, a potent regulator of bone marrow-derived cells, to load the HA nanoparticles (NPs), and delivered it by a sprayable hydrogel. GelMA/NP/miR-223* hydrogels could drive wound healing by not only triggering the resolution of the inflammatory phase but also promoting the formation of new vascularized skin tissue ( Figure 6B,C) [144].…”

“…(B) Synthesis illustration of the process for the formation of hyaluronic acid nanoparticle/miR-223*-laden GelMA hydrogels and the use of these adhesive hydrogels for wound healing. Adapted with permission from Gao et al[144]. (C) Images of the wounds treated with Dulbecco's phosphate-buffered saline (DPBS), GelMA, Neg miRNA incorporated GelMA, and miR-223* incorporated GelMAat days 0 and 12 of treatment.…”

“…* Images for animals at day 12 were acquired after removal of the silicon splint to highlight the extent of wound healing. Adapted with permission from Saleh et al[144].…”