Peptides are organic molecules consisting of chains of amino acids (ranging from about 2 to more than 50) linked by peptide bond. Peptides exhibit diverse pharmacological effects, including antimicrobial, antihypertensive, anti-inflammatory, and anticancer effects (Zhou et al., 2023[170]). A polypeptide is a longer, continuous, unbranched peptide chain, When its molecular mass reaches 10,000 Da or more, it is referred to as a protein (Feng et al., 2022[35]). Chains of 4 - 20 amino acids are termed oligopeptides, and include dipeptides, tripeptides, and tetrapeptides (Nasadyuk, 2021[97]). Peptides can be broadly classified according to their origin, chain length, biological role, and structural properties. Currently, peptides have attracted significant attention due to their ability to modulate diverse biological pathways and enhance cellular and molecular interactions (Gori et al., 2023[45]).

A notable example is the Arg-Gly-Asp (RGD) peptide sequence, which enhances fibroblast recruitment and migration, thereby accelerating the inflammatory and proliferative phases of wound healing (Chen et al., 2025[19]). The following sections further explain different classes of peptides with wound healing properties.

Antimicrobial peptides (AMPs) are a diverse group of naturally occurring molecules found in a wide range of organisms, including humans, toad, and mice. They are generally low in molecular weight, cationic, and amphipathic. Their amphipathic nature allow them to insert into the lipid bilayers and disrupt the microbial cell membranes (Feng et al., 2022[35]; Travkova et al., 2017[141]). AMPs typically act through mechanisms such as pore formation, membrane disintegration, and intracellular targeting (inhibition of protein or DNA synthesis), thereby providing broad-spectrum activity against bacteria, fungi, viruses, and even cancer cells (Le et al., 2017[76]).

AMPs contribute significantly to the wound-healing process through their antimicrobial, immunomodulatory, and regenerative properties (Nasseri and Sharifi 2022[98]). Their immunomodulatory functions include regulating cytokine production, influencing immune cell recruitment to the wound site, suppressing excessive inflammation by downregulating TNF-α, IL-6, and other pro-inflammatory mediator, and enhancing phagocytosis by modulating macrophage activity to facilitate the clearance of necrotic tissue and pathogens (Duan et al., 2022[29]), In addition, AMPs are highly effective against multidrug-resistant bacteria, as they target bacterial membranes, making it difficult for pathogens to develop resistance (Pervin and Hassan, 2021[105]).

Many AMPs adopt α-helical or β-sheet conformations that enhance their stability and interaction with bacterial membranes. Also, their relatively short peptide chains enable rapid diffusion through tissue, making them particularly effective for deep wound penetration (Zhang et al., 2025[164]). A notable example of an AMPs is Nisin, produced by Lactococcus lactis. It binds to lipid II on bacterial membranes, forming pores that lead to ion leakage and bacterial cell death. Its potent antimicrobial effect primarily targets Gram-positive pathogens, thereby minimizing wound infections and supporting tissue regeneration (Khan et al., 2023[68]). Other types of AMPs are summarized in Table 2(Tab. 2) (References in Table 2: Ahmad et al., 2024[5]; Araujo et al., 2022[9]; Cao et al., 2018[14]; David et al., 2016[23]; Di Grazia et al., 2015[27]; Dyrda-Terniuk and Pomastowski, 2023[30]; Fensterseifer et al., 2015[36]; Guryanova and Ovchinnikova, 2022[49]; Hoq et al., 2011[55]; Huang et al., 2017[58]; Khan, 2022[68]; Kim et al., 2015[72]; Kurek-Górecka et al., 2021[75]; Li et al., 2024[78]; Misra et al., 2024[91]; Nasseri and Sharifi, 2022[98]; Ong et al., 2020[103]; Shahzad, 2015[124]; Shini et al., 2022[126]; Song et al., 2019[131]; Takahashi et al., 2021[138]; Wang et al., 2018[143]; Wang et al., 2023[145]; Yacoub et al., 2020[155]; Yan et al., 2020[158]; Yang et al., 2024[159]; Yu et al., 2025[162]; Zhao et al., 2016[167]; Zhao et al., 2019[166]; Zhou et al., 2021[169]; Zhou et al., 2023[170]).

Animal-derived peptides have been shown to accelerate wound healing, prevent scar formation, and contribute to infection control at the wound site. As they are derived from natural animal proteins, these peptides are generally considered safe and reliable. They are sourced from a wide range of animals, including amphibians, insects, marine organisms, and mammals (Fan et al., 2024[33]).

Structurally, animal-derived peptides are typically composed of short amino acid sequences (ranging from 12-50 residues) that may be linear or cyclic and often adopt secondary structures such as α-helices and β-sheets. They are amphipathic, containing both cationic and hydrophobic domains, which enable them to interact with microbial membranes and as well as host cells, thereby exerting antimicrobial and wound-healing effects (Sun et al., 2024[137]; Ma et al., 2024[83]). For example, Bovine Lactoferrin (BLF) is an iron-binding glycoprotein derived from bovine colostrum, with each lobe capable of binding a single Fe³⁺ ion. Its structure enables it to inhibit microbial growth by sequestering iron, which bacteria need to survive, and by disrupting microbial membranes. In wound healing, BLF modulates inflammation by downregulating key cytokines such as TNF-α and IL-6, and promotes ECM remodeling through the regulation of MMPs. It exerts positive effects across all phases of wound healing, homeostasis, inflammatory, proliferative, re-epithelization and remodeling phase (Dyrda-Terniuk and Pomastowski, 2023[30]; Shini et al., 2022[126]). Other types of animal-derived peptides are summarized in Table 2(Tab. 2).

Plant-derived peptides are typically short sequences of 2-20 amino acids with molecular weights below 3 kDa, and are generated through the enzymatic hydrolysis of plant proteins (Nicolas-Espinosa et al., 2022[100]). Their small size and structural composition often featuring cationic and hydrophobic residues enable them to interact with and penetrate biological membranes. This facilitates various therapeutic effects, including modulation of inflammation, reduction of oxidative stress, antimicrobial activity, stimulation of cell proliferation, and remodeling of ECM, all of which are crucial to the skin repair process (Nirmal et al., 2024[102]; Fan et al., 2022[32]). In a burn-injury rat model, oral administration of soybean-derived peptides downregulated NF-κB pathway activation and reduced neutrophil and macrophage infiltration at wound sites. Treated animals also exhibited enhanced angiogenesis, indicated by elevated CD31 expression, and accelerated healing, achieving 67 % wound closure compared with 41 % in control animals by the eighth week (Zhao et al., 2019[166]). Other types of plant derived peptides are summarized in Table 2(Tab. 2).

In addition to natural peptides, synthetic peptides have gained a considerable attention as bioactive agents for accelerating wound healing. Their small size, ease of synthesis, and high tunability make them versatile tools that can be tailored for specific biological functions. They can be rationally designed or derived from natural protein sequences to target specific pathways involved in wound repair (Guan et al., 2022[46]; Md Fadilah et al., 2024[88]).

A notable example is A7-1, a synthetic peptide derived from a 13-residue sequence in silk fibroin, identified for its adhesive properties and ability to support early wound regeneration. A study demonstrated that topical application of A7-1 in mice accelerated early angiogenesis and granulation tissue formation, potentially through stabilizing local growth factor gradients (Jung et al., 2024[66]). Additional engineered peptides and their mechanisms of action are summarized in Table 3(Tab. 3) (References in Table 3: Chung et al., 2017[21]; Dzierżyńska et al., 2023[31]; Gawande et al., 2014[40]; Gomes et al., 2017[44]; Jiang et al., 2023[64]; Jung et al., 2024[66]; Liu et al., 2024[82]; Mndlovu et al., 2023[92]; Nakagami et al., 2017[96]; Pfalzgraff et al., 2016[106]; Singh et al., 2025[128]). Furthermore, to provide a concise overview of the strength of evidence, Table 4(Tab. 4) (References in Table 4: Ansari et al., 2021[8]; Cappiello et al., 2019[16]; Carretero et al., 2008[17]; Di Grazia et al., 2015[27]; Dzierżyńska et al., 2023[31]; Guarnera et al., 2010[47]; He et al., 2019[50]; Heunis et al., 2013[52]; Hoq et al., 2011[55]; Hu et al., 2023[57]; Jaramillo et al., 2023[62]; John et al., 2023[65]; Karimi et al., 2021[67]; Kim et al., 2015[72]; Koohzad and Asoodeh, 2023[73]; Lebedeva et al., 2017[77]; Liu et al., 2014[80]; Liu et al., 2014[81]; Mahlapuu et al., 2021[84]; Mndlovu et al., 2023[92]; Mouritzen et al., 2019[95]; Nakagami et al., 2017[96]; Philp et al., 2004[107]; Pickart et al., 2015[108]; Radek et al., 2008[114]; Raheem et al., 2024[116]; Rivera-Sanchez et al., 2025[117]; Shini et al., 2022[126]; Simonetti et al., 2008[127]; Song et al., 2025[129]; Sun et al., 2019[136]; Tomioka et al., 2014[140]; Uşaklıoğlu and Çakan, 2023[142]; Wigger-Alberti et al., 2012[148]; Yaraguppi et al., 2023[160]; Zhang et al., 2020[165]; Zhao et al., 2019[166]; Zhou et al., 2021[169]) summarizes wound healing peptides for which results have been independently reproduced across different study types.

Peptide-based hydrogels can enhance nearly all phases of wound healing. For example, during the homeostasis phase, they can aid by rapidly forming a physical barrier and promoting clot formation. In a rat bleeding model, h9e peptide solution achieved hemostasis 82 % faster than a commercial hemostatic agent (Celox™) by rapidly gelling and concentrating platelets and clotting factors at the bleeding site (Guan et al., 2022[46]; Carter et al., 2021[18]).

Additionally, peptide-based hydrogels can facilitate the inflammatory phase through their intrinsic antimicrobial and immunomodulatory functions (Kharaziha et al., 2021[70]). A notable example is a hydrogel functionalized with the thrombin-derived peptide TCP-25, designed to address bacterial infection and inflammation. TCP-25 not only exhibits broad-spectrum antimicrobial activity but also binds bacterial endotoxins (e.g., lipopolysaccharide) neutralizing their inflammatory effects. In infected wound models, a TCP-25 peptide hydrogel eradicated Staphylococcus aureus and Pseudomonas aeruginosa while concurrently reducing pro-inflammatory cytokine levels in the local tissue (Dahlman et al., 2021[22]).

Moreover, peptide hydrogels can significantly enhance the proliferative phase by serving as a bioactive scaffold for cell growth (Im et al., 2018[60]). Because peptide matrices closely resemble native ECM, they promote keratinocyte and fibroblast migration into the wound and support their proliferation (Xiang et al., 2020[152]). For example, in a study using a chitosan-based film-forming gel containing tyrothricin, researchers observed accelerated healing in rat wound models, including burns, abrasions, and excisions. Treated wounds showed enhanced granulation tissue formation and epithelialization compared with control groups. Additionally, histological analyses revealed increased fibroblast proliferation and angiogenesis, leading to a faster and smoother transition to tissue regeneration (Kim et al., 2015[72]).

In the final remodeling phase, peptide hydrogels can influence remodeling and improve healing in earlier phases, eventually reducing scar formation (Song et al., 2020[130]). For instance, a study investigating a resveratrol-loaded self-assembling peptide hydrogel, RADA-PDGF2, in a rat model demonstrated its beneficial effects on wound healing. Treated wounds displayed more organized collagen deposition and nearly normal epidermal architecture at the completion of healing, with minimal scar tissue. Furthermore, histological analyses showed that collagen fibers in treated wounds were aligned similarly to those in uninjured skin, in contrast to the disorganized bundles typically observed in scar tissue (Deptuła et al., 2023[26]). Thus, peptide-based hydrogels not only accelerate the early stages of healing but also improve the overall quality of repair. Table 5(Tab. 5) (References in Table 5: Abbasi Aval et al., 2022[2]; Capella-Monsonís et al., 2020[15]; Gil et al., 2022[42]; Guiotto et al., 2024[48]; Michaels et al., 2024[89]; Mohapatra et al., 2021[93]) lists peptide-based hydrogels that are available in the current market.

Recent research has achieved remarkable advances in the functionalization and performance of peptide hydrogels for wound healing. For example, in 2023, Huang et al., engineered an “all-peptide” hydrogel using modified γ-polyglutamic acid and RGD-containing peptides, which could be 3D-printed with living cells. Endothelial cells overexpressing VEGF were printed within this peptide matrix, creating a living scaffold that continuously released VEGF, promoted angiogenesis. In diabetic wound models, this VEGF-eluting peptide hydrogel significantly accelerated wound closure and enhanced tissue regeneration by reducing inflammation and hypoxia (Huang et al., 2023[59]).

In 2025, Chen et al. reported a self-healing hydrogel composed of food-derived peptides that simultaneously addresses infection, inflammation, and hemostasis. The hydrogel was formed by cross-linking egg-white proteins with oxidized polysaccharides and incorporating a copper-bound tripeptide (GHK-Cu) known for its regenerative activity. The resulting gel demonstrated broad-spectrum antibacterial and anti-inflammatory effects and rapidly stopped bleeding by adhering to tissues (Filipczak et al., 2021[37]). In infected wound models, the GHK-Cu peptide hydrogel significantly accelerated healing, achieving ~95 % wound closure by day 12 compared with 65 % in controls, primarily by promoting neovascularization and tissue regeneration (Chen et al., 2025[20]).

Another advancement is the development of dual-action anti-infective peptide hydrogels. Puthia et al. (2020[110]) created a hydrogel incorporating TCP-25, a peptide derived from thrombin that not only kills bacteria but also neutralizes inflammatory endotoxins (PAMPs). In mouse and pig wound models, a TCP-25 hydrogel eradicated MRSA and Pseudomonas aeruginosa infections and significantly reduced pro-inflammatory cytokines in the wound environment, thereby expediting healing (Puthia et al., 2020[110]). This study highlights a strategy of functionalizing a polymer hydrogel with a host-defense peptide to create a dual-action dressing capable of reducing bacterial biofilm and excessive inflammation.

Peptide hydrogels are also being designed to respond to wound microenvironmental cues. For example, pH-switchable peptide assemblies have been developed to release therapeutics in infected wounds (Li et al., 2022[79]). Many peptide hydrogels are injectable or sprayable, leveraging their shear-thinning behavior. A notable property of certain peptide formulations (e.g., the UD-developed peptides in G4Derm) is their ability to be applied as a liquid and rapidly gel in situ upon contact with tissues, conforming to irregular wound shapes (Roberts, 2024[119]). This shear-thinning and rapid recovery behavior is particularly advantageous for filling deep or tunneling wounds where pre-formed dressings cannot reach. Such advancements greatly enhance the applicability of peptide hydrogels in complex wound scenarios. Table 6(Tab. 6) (References in Table 6: De Leon-Oliva et al., 2023[24]; Foley and Lau, 2016[38]; Hosoyama et al., 2019[56]; Mandla et al., 2019[86]; Puthia et al., 2020[110]; Robert et al., 2022[118]; Roberts, 2024[119]; Seow et al., 2016[123]; Wei et al., 2019[147]; Xiao et al., 2016[153]; Yadav et al., 2022[156]; Zhang et al., 2024[163]; Zhou et al., 2022[168]) summarizes additional recent progress in peptide hydrogel research.

Additionally, a range of peptide-containing hydrogels is currently under investigation for skin regeneration. For example, Granexin^® Gel (containing αCT1) has advanced to Phase III trial in diabetic foot ulcers, while SLI-F06, a fibromodulin-mimetic peptide hydrogel, has completed Phase I/IIa testing in post-surgical scars (Freedman et al., 2023[39]). The emerging clinical pipeline of peptide hydrogels ranging from anti-scarring agents to antimicrobial and angiogenic dressings reflects a rapidly maturing field poised to deliver novel bioactive wound therapies. Examples of hydrogels currently in clinical trials but not yet approved by regulatory agencies are presented in Table 7(Tab. 7) (References in Table 7: Attik et al., 2023[10]; Banerjee et al., 2025[11]; Deliencourt- Godefroy et al., 2025[25]; Freedman et al., 2023[39]; Gelain et al., 2021[41]; Niemeyer et al., 2022[101]; Yaguchi et al., 2021[157]; Ye et al., 2022[161]).

The authors declare that there are no commercial or financial relationships that could be construed as a potential conflict of interest in the preparation and publication of this review.

No AI tool was used for the writeup of this manuscript.

Rafl M. Kamil: Conceptualization, Methodology, Data curation, Formal analysis, Writing original draft. Shaik Nyamathulla: Conceptualization, Funding acquisition, Resources, Supervision, Review and editing. Syed Mahmood: Conceptualization, Resources, Supervision, Review and editing.

The authors would like to express their utmost gratitude and appreciation to Universiti Malaya for funding a research project (Universiti Malaya Research Excellence grant -UMREG071-2024) related to the peptide-based hydrogels for wound healing. Further, the work on peptides is supported by the Ministry of Higher Education, Malaysia by the Fundamental Research Grant Scheme (FRGS) grant (FP-048-2020) to investigate the role of peptides in chronic wounds.