Introduction
Wound management affects more than 20 million individuals worldwide and imposes a significant financial burden on healthcare systems.(p1) Wound healing is an essential and complicated biological mechanism vital for restoring the integrity of damaged tissue. There are different stages of wound healing, including hemostasis, inflammation, proliferation, and remodeling. The various kinds of cellular and molecular events can regulate each phase to ensure tissue repair and regeneration. Upon injury, a reduction in bleeding occurs upon blood vessel constriction, followed by platelet aggregation and clot formation to close the wound. This phase involves factors such as thrombin and fibrin, providing a temporary matrix for cell migration.(p2) Then, immune cells such as neutrophils and macrophages can infiltrate the wound site to remove debris and pathogens. The release of pro-inflammatory cytokines, including tumor necrosis factor (TNF)-α and interleukin (IL)-1β, occurs to enhance angiogenesis and recruit fibroblasts and keratinocytes.(p3) This phase involves the formation of granulation tissue, characterized by the proliferation of fibroblasts, endothelial cells, and keratinocytes. Fibroblasts produce extracellular matrix (ECM) components such as collagen, whereas endothelial cells generate new blood vessels (angiogenesis). This phase is mainly controlled by growth factors such as vascular endothelial growth factor (VEGF), transforming growth factor (TGF)-β, and epidermal growth factor (EGF).(p4) Within weeks to months, ECM remodeling occurs to recover tissue strength and function. The reorganization of collagen fibers occurs, and the remaining cells undergo apoptosis. Matrix metalloproteinases (MMPs) and their inhibitors such as tissue inhibitors of metalloproteinases (TIMPs) contribute to the regulation of this process, preserving a balance between synthesis and degradation.(p5) Chronic wounds, such as diabetic ulcers, originate from disruptions in these stages, impairing angiogenesis and causing persistent inflammation or infection. Progress in wound care using bioactive dressings and stem cell therapy could address such challenges.(p6) Figure 1 demonstrates the general steps of wound healing.
Chronic wounds are defined by an inability to advance through the standard phases of healing, including coagulation, inflammation, cellular proliferation, matrix repair, and epithelialization, and they frequently remain stagnant in the inflammatory phase. In contrast to acute wounds, chronic wounds possess varied and distinct etiologies, including venous leg ulcers resulting from venous hypertension caused by valve dysfunction, diabetic foot ulcers arising from repetitive pressure on neuropathic and ischemic feet, and pressure ulcers stemming from prolonged mechanical stress in immobile patients. Notwithstanding standard therapies such as compression therapy, unloading, and pressure relief, many chronic wounds remain unhealed because of underlying systemic factors, including dysfunctional fibroblasts in diabetes mellitus, immunodeficiencies, malnutrition, obesity, substance misuse, and smoking. The wounds exhibit heightened concentrations of cytokines and MMPs, and sustained neutrophilic activity, resulting in ongoing inflammation and tissue injury. The disparity between destructive and reparative processes in the wound environment hinders healing, highlighting the necessity for focused treatment techniques that can adjust the inflammatory response and restore balance in tissue repair mechanisms.(p8) Moreover, in chronic wounds such as diabetic states, it is suggested that the epidermis becomes thinner.(p9)
Given the growing prevalence of chronic wounds, advances in the development of wound healing materials could revolutionize healthcare delivery and improve the treatment of chronic wounds, such as diabetic foot ulcers, venous leg ulcers, and pressure sores. Such wounds are not able to proceed through the normal healing stages in conditions such as diabetes, poor circulation, or persistent infections, resulting in high healthcare costs and a high risk of complications, including amputations.(p10) The introduction of advanced wound care materials could improve and address such challenges by providing optimal healing conditions, reducing infection risks, and promoting tissue regeneration. Conventional wound dressings, such as gauze, are not capable of preserving moisture, controlling exudation, or delivering bioactive agents, reducing their efficacy in wound management. In contrast, advanced and smart materials, including hydrogels, alginates, and hydrocolloids, provide a moist wound environment that can significantly improve cell migration and proliferation.(p11) Additionally, bioactive dressings incorporated with growth factors, antimicrobial agents, or stem cells can induce wound healing. Silver-incorporated dressings can exert antibacterial activity, whereas collagen-based scaffolds improve tissue regeneration.(p12) The introduction of nanobiotechnology has further revolutionized wound management through smart and advanced dressings responding to the wound conditions, such as pH or temperature changes, to release therapeutic agents in a sustained manner.(p13) Such innovations are vital for enhancing wound healing and decreasing the need for dressing alterations. The economic burden of chronic wounds is remarkable, with annual costs in the USA alone estimated at $25 billion,(p14) providing a warning and requiring novel methods for wound management. Such costs can be decreased by the application of advanced wound healing materials to decrease hospital stays, thereby reducing complications and improving outcomes. Given population aging and chronic disease, the application of these materials is important in the field of wound management and healing.
Peptides are ideal candidates for wound healing because of their ability to regulate cellular processes, enhance tissue regeneration, and suppress infections. These short amino acid chains are bioactive and capable of mimicking the functions of growth factors, cytokines, and antimicrobial agents, endowing them with significant value in advanced wound management. Peptides such as arginine–glycine–aspartic acid (RGD) and lysine–threonine–threonine–lysine–serine (KTTKS) might improve fibroblast and keratinocyte migration, which are vital for re-epithelialization and ECM formation. RGD peptides have been demonstrated to bind to integrin receptors on cell surfaces, enhancing cell adhesion and proliferation.(p15) Antimicrobial peptides (AMPs), such as defensins and cathelicidins, can suppress infections in chronic wounds, and such peptides are beneficial for disrupting bacterial membranes and reducing biofilm formation and antibiotic resistance. AMPs including leucine, leucine 37 (LL-37) have remarkable efficacy against multidrug-resistant (MDR) pathogens, highlighting their efficacy compared with traditional antibiotics.(p16) Inflammatory responses can be regulated by peptides through suppressing pro-inflammatory cytokines and resolving inflammation. Thymosin β4 has been shown to reduce inflammation and enhance angiogenesis, thus accelerating wound healing and closure.(p17) Peptides such as VEGF-mimetic peptides can induce the formation of new blood vessels, thereby improving the enrichment of oxygen and nutrients at the wound site. Such activity is vital for chronic wounds in which healing is delayed by impaired angiogenesis. Peptides can also be incorporated into advanced wound dressings or hydrogels for prolonged release, improving their therapeutic efficacy. Peptide-loaded nanoparticles have been developed to deliver growth factors directly to the wound site, thus improving bioavailability and reducing systemic side effects. Figure 2 demonstrates the various materials and peptide-based systems used for wound healing acceleration.
Recent studies highlight the significant therapeutic potential of small bioactive peptides in expediting wound healing and tissue regeneration. CyRL-QN15, a small yet potent peptide, greatly improved wound healing in mice by downregulating miRNA-365-2-5p, thereby upregulating sirtuin 1 (SIRT1) and forkhead box O1 (FOXO1) and inhibiting signal transducer and activator of transcription 2 (STAT2), which facilitated keratinocyte proliferation and decreased inflammation. In diabetic mice, CyRL-QN15 enhanced follicle regeneration by activating the Frizzled-7/β-catenin signaling pathway in hair follicle stem cells, promoting the production of cellular myelocytomatosis oncogene (c-MYC), cyclin D1, and lymphoid enhancer binding factor 1 (Lef1). Likewise, the amphibian-derived peptide Andersonin-W1 (AW1) demonstrated significant prohealing properties by interacting with Toll-like receptor 4 (TLR4) and regulating the nuclear factor kappa B (NF-κB) signaling pathway in macrophages, thus managing inflammation and facilitating macrophage polarization, re-epithelialization, angiogenesis, and granulation tissue development. These findings collectively underscore the distinctive and multifaceted roles of peptides such as CyRL-QN15 and AW1 in enhancing the treatment of chronic and diabetic skin lesions.(p18),(p19),(p20)
In addition to the promising features of peptide-based therapies, a systematic comparison with conventional wound management strategies such as antibiotics and growth factors is critical to contextualize their clinical value. Traditional antibiotics, although effective against acute bacterial infections, often exhibit poor tissue penetration and face growing antimicrobial resistance, thereby limiting their efficacy in chronic wound environments. In contrast, AMPs disrupt bacterial membranes via physical mechanisms, significantly reducing the risk of resistance and exhibiting broader activity against biofilms. Similarly, growth factors like VEGF and EGF promote angiogenesis and cellular proliferation but are limited by their instability, high production costs, and susceptibility to enzymatic degradation in wound environments. Peptide mimetics of these growth factors can be engineered for enhanced stability and targeted activity, offering improved bioavailability and lower immunogenicity. Furthermore, peptide-based materials demonstrate superior biocompatibility, tunable degradation kinetics, and the potential for multifunctional integration, simultaneously offering antimicrobial, anti-inflammatory, and pro-regenerative functions. These distinct advantages underscore the therapeutic efficacy and molecular targeting specificity of peptide-based strategies, positioning them as promising next-generation alternatives or complements to conventional wound care modalities.
Section snippets
Peptides in wound healing: mechanisms and functions
Peptides have demonstrated many features, including antimicrobial, cell-penetrating, angiogenic, anti-inflammatory, and ECM-mimetic properties, improving their suitability for application for wound healing. These small and versatile molecules can target different stages of the wound healing process, thereby enhancing their value in wound treatments. Peptides exert versatile functions in wound healing, targeting various stages of the process from infection control to tissue regeneration. AMPs
Concluding remarks and future perspectives
Peptide-based methodologies have been considered as novel innovations in advanced wound healing to tackle the complex nature of chronic and non-healing wounds. The intrinsic biocompatibility, specificity, and multifunctionality of peptides make them optimal candidates for influencing essential facets of wound healing, such as antibacterial activity, angiogenesis, anti-inflammatory responses, and ECM remodeling. The present review has highlighted the various processes through which peptides can
Author contributions
C.Z., Writing – original draft, Writing-review editing; L.M., Writing – original draft, Writing-review editing; G.S., Conceptualization, Writing-review editing; J.W., Conceptualization, Writing-review editing; B.L., Conceptualization, Writing-review editing.
Declarations of interest
No interests are declared.
Acknowledgments
J.W. is supported by the Shenzhen Science and Technology Program (Grant No. RCBS20231211090733052, JCYJ20240813150221028), the Guangdong Basic and Applied Basic Research Foundation (Grant No. 2023A1515111044, 2025A1515012665), and the Research Start-up Fund of Post-doctoral of SAHSYSU (Grant No. ZSQYRSFPD0067).
Gautam Sethi is an associate professor in the Department of Pharmacology, National University of Singapore. The focus of his research has been to elucidate the mechanism (s) of activation of oncogenic transcription factors and to identify novel inhibitors of these proteins for cancer therapy.