GAS6 mRNA Hydrogel Promotes Wound Healing and Reduces Scarring in Animal Models
Background
Deep skin injuries can leave fibrotic scars even after the wound has healed. A study published in Nature Communications reported that locally delivering messenger RNA (mRNA) encoding the GAS6 protein to wounds could promote healing and lower scar measures in mice, rabbits, and minipigs. The study did not establish treatment efficacy in humans or complete scar elimination.
The researchers focused on signaling between macrophages and fibroblasts. Inflammatory fibroblasts can release signals that recruit immune cells and sustain inflammation. Reduced GAS6 was observed in public gene-expression data from human wounds and in animal and cell experiments, prompting the researchers to test a strategy to replenish this signal. The human data involved an analysis of gene-expression changes, not a clinical trial testing treatment efficacy.
Key findings
GAS6 mRNA was packaged in lipid nanoparticles (LNPs) and incorporated into a thermosensitive hydrogel for local application to wounds. A gel that is liquid at low temperatures and solidifies at body temperature was used to help the delivery system remain at the wound site and deliver mRNA. In mouse wounds, GAS6 protein expression peaked on day 3 after surgery and then declined.
In cell experiments, efferocytosis—the engulfment and removal of dead cells by macrophages—increased. When culture medium from macrophages treated with LNP-GAS6 mRNA was transferred to fibroblasts, expression of the inflammation-related genes Csf1 and Cxcl12 also fell. Direct treatment of fibroblasts with LNP-GAS6 mRNA, by contrast, did not significantly change expression of those genes. This supports the interpretation that macrophage-derived signals lowered the fibroblasts’ inflammatory response; it is distinct from a finding that fibroblast numbers directly decreased.
Wound healing and scar reduction were also observed in animal studies. In mice, scar width at 30 days after surgery was 71.61% lower than in controls; in rabbit ears, the scar elevation index at day 60 was 54.09% lower. The scar elevation index is the ratio of scar height to the thickness of the surrounding normal skin. In a Bama minipig study involving six animals in total, the formulation was applied to full-thickness skin wounds 15 mm in diameter. At day 35, scar area was 53.69% smaller than in the gel-only group. The gel-only group was the comparator for this reduction. A human epidermal growth factor gel was included as a separate comparator, and the measures and observation times differed across the three animal models.
Meaning and outlook
The study presents a preclinical strategy to reduce later scar formation by modulating both macrophage clearance of dead cells and inflammatory signaling early after injury. The treatment was applied early after wounding; its ability to remove already formed scars was not assessed. The design, which combines local retention of an mRNA delivery system with transient protein expression, also provides a basis for further development.
However, reduced scar measures in animals cannot be taken as evidence of scar-free healing in people. The researchers also noted that the distribution of the TAM receptor family (TYRO3, AXL, and MERTK), through which GAS6 acts, differs among species, and that the role of each receptor in human skin needs further study. The appropriate human dose, efficacy, and long-term safety remain unknown.
This account of the research is based on the provided full paper and bibliographic record and abstract.
Deep lacerations in adult mammals frequently result in fibrotic scarring, a process intensified by inflammatory fibroblasts that amplify immune responses. Early intervention targeting the interaction between immune cells and fibroblasts shows therapeutic promise. This study highlights GAS6 as a pivotal regulator in this interaction and demonstrates its therapeutic modulation using a precisely timed lipid nanoparticle (LNP)-mRNA hydrogel system. Specifically engineered LNP-GAS6 mRNA enhances macrophage phagocytosis and suppresses inflammatory fibroblasts, encapsulated within a thermally sensitive hydrogel for targeted application. Across murine, rabbit ear, and Bama minipig wound models, this treatment markedly accelerated wound closure while significantly reducing fibrotic scarring. These findings indicate that restoring GAS6 signaling through mRNA delivery facilitates scarless healing, presenting a promising therapeutic strategy for fibrotic skin conditions.
A possible application in further development would be to use a local mRNA delivery system to modulate early inflammation when treating deep skin wounds, with the aim of reducing subsequent scar formation. Because the approach supports macrophage clearance of dead cells and lowers inflammatory signaling in fibroblasts, it offers a basis for evaluating both wound-closure speed and the resulting scar. The findings do not establish that the treatment removes existing scars or is effective in people. Clinical development would need to establish the timing and dose of administration, how long expression persists at the wound site, and long-term safety, and determine whether treatment leads to actual scar reduction and recovery of skin function.