The wound healing cascade is a precisely orchestrated and meticulously executed biological process, encompassing numerous biochemical and cellular responses that are regulated by the body’s immune system to restore the integrity of skin and subcutaneous tissues. It is divided into four highly interrelated and partially overlapping phases: hemostasis, inflammation, proliferation, and remodeling (Yuan et al., 2023) In diabetic patients, underlying pathological factors such as neuropathy, peripheral artery disease, and persistent hyperglycemia disrupt the normal wound repair process, leading to stalled healing and increasing vulnerability to infection. Once infection occurs, it combines with oxidative stress and chronic inflammation triggered by excessive reactive oxygen species (ROS), further exacerbating tissue damage, infection severity, and ulcer formation/progression. These interconnected mechanisms form a vicious cycle that drives non-healing wounds to ultimately culminate in DFUs (Dayya et al., 2022; Deng et al., 2023).

The hemostatic phase commences immediately after injury and may persist for several hours, aiming to control bleeding and restrict systemic microbial dissemination. The body initiates primary hemostasis first, during which vasoconstriction occurs instantaneously, and platelets are activated and aggregated to form a provisional platelet plug. Secondary hemostasis begins with the activation of the coagulation cascade, generating thrombin that catalyzes the conversion of fibrinogen to fibrin. The cross-linking of fibrin into a mesh that envelops the platelet aggregate, culminating in the formation of a stable clot, signifies the conclusion of the hemostatic phase (Wilkinson and Hardman, 2020; Singer, 2022). Subsequently, activated platelets release growth factors including platelet-derived growth factor (PDGF) and transforming growth factor-beta (TGF-β), which recruit inflammatory cells such as neutrophils to infiltrate the wound site. This cellular infiltration signifies the commencement of the inflammatory phase of healing (Jarić et al., 2018; Szułdrzyński et al., 2020). In DFUs, healing impairment originates from hemostatic dysfunction (Figure 1A). Hyperglycemia disrupts platelet aggregation, while advanced glycation end-products (AGEs) suppress fibrinogen function, impairing fibrin-platelet cross-linking and reducing clot stability. Concurrently, platelet hyperactivation promotes microthrombosis and hypoperfusion, dysregulating the coagulation cascade (Gawlowski et al., 2007; Brings et al., 2017; Hicks and Selvin, 2019; McDermott et al., 2022).

The inflammatory phase initiates almost concurrently with hemostasis, typically spanning 1–4 days post-injury. However, its duration may extend to weeks or even years due to underlying pathologies (Tomic-Canic et al., 2020). During this stage, neutrophils may recruit monocytes by secreting several inflammatory factors (IL-1, IL-6, IL-8, IL-10) and the chemokine MCP-1 to regulate the inflammatory response (Singer, 2022; Peña and Martin, 2024). Subsequently, infiltrating monocytes differentiate into M1 macrophages (the predominant cell type during periods of inflammation.) M1 macrophages exert antimicrobial activity primarily by recognizing pathogen-associated modifier proteins (PAMPs) and damage-associated modifier proteins (DAMPs) and by releasing NO, ROS, and pro-inflammatory cytokines to clear pathogens and cellular debris. Ultimately, the sign of inflammation subsiding is the clearance of neutrophils through phagocytosis by macrophages or re-entry into the vascular system (Hassanshahi et al., 2022; Sharifiaghdam et al., 2022). As shown in Figure 1B, whereas the key factor contributing to the delayed healing of DFUs wounds is the persistent overpresence of M1 macrophages and their subsequent inability to convert to the M2 repair phenotype, which amplifies the stimulatory response to cytokines (Aitcheson et al., 2021; Tang et al., 2022). Under hyperglycemic conditions, neutrophils continuously release ROS and stimulate the upregulation of peptidyl arginine deaminase 4 (PAD4), which leads to the overproduction of neutrophil extracellular traps (NETs) and damage to tissue cells (Yang et al., 2023; Zhang Y. et al., 2025). This activates pathways such as NF-κB and promotes the release of inflammatory factors, resulting in local microcirculation disorders that further lead to increased inflammation and vascular and neurological tissue lesions in the ulcerated area (Li et al., 2023; Huang W. et al., 2020; Yang et al., 2020). Important at this stage is an impaired immune response, which will not prevent colonization by pathogenic bacteria, and an excess of AGEs will lead to microbial membrane formation (Liu C. et al., 2020; Xie et al., 2020). In addition, AGEs bind to receptors for advanced glycation end products (RAGE)on various cell types, activating multiple signaling pathways including MAPK/ERK, TGF-β, JNK, and NF-κB. This process increases intracellular oxidative stress, exacerbates local inflammatory responses, and ultimately impedes the transition to subsequent healing phases (Huijberts et al., 2008; Khalid et al., 2022). How to dynamically regulate the timing of the transition from the inflammatory to the proliferative phase is a current difficulty in the treatment of DFUs (Zhou et al., 2022). Concurrently,the disruption of endogenous antioxidant defense mechanisms constitutes a critical pathogenic factor in the development of DFUs (Deng et al., 2021).

After hemorrhage and inflammation are controlled, a proliferative phase, which is longer and can last for several weeks, takes place. The beginning of the proliferative phase is marked by the migration of fibroblasts into the wound, proliferation, and secretion of extracellular matrix (ECM) components to build granulation tissue as a new cellular scaffold (Raziyeva et al., 2021). Angiogenesis is another important process in this phase, where the macrophage phenotype changes from an inflammatory state (type M1) to a healing state (type M2), releasing healing cytokines: PDGF, epidermal growth factor (EGF), and vascular endothelial growth factor (VEGF), which promote deposition of the ECM and repair of broken blood vessels and formation of new blood vessels (Peng et al., 2020). Keratinocytes ultimately achieve epithelial regeneration by secreting local growth factors TGF-α, TGF-β, and keratinocyte growth factor (KGF/FGF 7), as well as by being influenced by mechanical factors (“free edge effect”) (Huang et al., 2023). As shown in Figure 1C, in DFU wounds, the persistence of M1 macrophages causes excessive release of TNF-α and promotes the release of Matrix Metalloproteinase-9 (MMP-9) rom keratinocytes to continuously degrade the ECM, which impairs the migratory ability of keratinocytes and thus prevents the re-epithelialization of the ulcerated wounds (Deng et al., 2024). High accumulation of AGEs leads to fibroblast senescence and is not regulated by the migration stimulator TGF-β, inhibiting their migration into the wound (Deng et al., 2023; Huang et al., 2023). Oxidative stress from hyperglycemia-induced ROS surge elevates oxygen consumption, suppressing hypoxia-inducible factor-1α (HIF-1α) and downstream VEGF expression. This disruption of angiogenic signaling cascades culminates in reduced neovascularization, perpetuating microcirculatory deficits in ulcerated tissues (Catrina and Zheng, 2016).

The remodeling phase is the final stage of wound healing and can last from weeks to years after injury. Fibroblasts upregulate the expression of type I collagen, and macrophages release MMPs into the deposited ECM, causing wound contraction and tissue remodeling through protein hydrolysis and endocytosis. Furthermore, as the ECM subsides, the dense connective tissue is replaced by newborn natural tissue, maintaining normal tissue function of the skin (Sutherland et al., 2023). Finally, as apoptosis of vascular cells and myofibroblasts heralds the end of healing, the conversion of cell-rich granulation tissue into collagen-filled cells results in scarless healing (Eckes et al., 2010; Reinke and Sorg, 2012). As shown in Figure 1D, during the tissue remodeling phase of DFUs, the persistent high-glycemic environment and excessive inflammatory response resulted in high expression of MMPs, leading to excessive degradation of ECM and stagnation of collagen remodeling (Fu et al., 2022). As shown in Figure 1D, persistent ROS and an inflammatory microenvironment induce premature senescence of fibroblasts. On one hand, this significantly inhibits their ability to differentiate into myofibroblasts, preventing the wound from actively contracting. On the other hand, it severely impairs collagen synthesis function, resulting in an insufficient total amount of newly synthesized collagen (Darby et al., 2014). Meanwhile, the accumulation of AGEs disrupts collagen fibers through irreversible covalent cross-linking, causing abnormal cross-linking and excessive degradation of the ECM. This leads to the inability of myofibroblasts to arrange properly at the wound site, ultimately resulting in wound closure failure (Asadipooya and Uy, 2019; Yang Y. et al., 2024).

Multiple biological responses affect wound healing in DFUs, including persistent inflammation, oxidative damage, impaired angiogenesis, apoptosis, and aberrant ECM deposition. Among these, the vicious cycle formed by mutual reinforcement of oxidative stress and chronic inflammation is identified as a primary risk factor for delayed wound healing in DFUs (Jeffcoate et al., 2024; Xiao F. et al., 2024; Da Silva et al., 2025). Following organismal injury, a modest inflammatory response is a key defense mechanism to clear pathogens and initiate repair (Huang et al., 2022). However, insufficient inflammation weakens the skin’s antimicrobial barrier and increases the risk of infection. The loss of the natural barrier makes it easier for microorganisms outside the wound to invade the skin tissue and trigger inflammation (Uberoi et al., 2024; Zielińska et al., 2023). Conversely, DFUs often exhibit a hyperinflammatory microenvironment marked by excessive pro-inflammatory cytokine release and ROS overproduction. These factors not only induce oxidative cellular damage but also promote local ischemia and hypoxia, further exacerbating ulcer progression. Importantly, diabetic wounds are frequently prone to infection, which is closely associated with biofilm formation and persistent inflammation. Compared to ordinary chronic wounds, pathogenic microorganisms on DFU wounds exhibit a higher propensity to form biofilms, thereby inducing excessive inflammation. Moreover, patients with DFUs suffer from impaired immune responses, leading to microbial dysbiosis in the wound microenvironment (Jnana et al., 2020a; Mudrik-Zohar et al., 2022). The core mechanism involves biofilm formation by multiple pathogens. The microbial communities in DFUs predominantly consist of Gram-positive and Gram-negative bacteria, including Staphylococcus aureus, Streptococcus spp., and Pseudomonas aeruginosa. Among these, the biofilm structures of S. aureus and P. aeruginosa can physically impede immune cell infiltration. More critically, once microbial biofilms mature, the embedded microorganisms exhibit remarkable resistance and evasion capabilities (evading phagocytosis and clearance by immune cells), posing a fundamental barrier to sustained wound infection and impaired healing (Pouget et al., 2020; Lou et al., 2025).

Currently, the treatment of choice for DFU infections is antibiotic therapy. However, due to the limitations of the antibiotic antimicrobial spectrum, the cost of treatments aimed at killing all microorganisms in the wound is significant and is detrimental to wound healing in DFUs (Jnana et al., 2020b; Liu C. et al., 2020). A recent clinical study supports this notion: metagenomic shotgun sequencing analysis of wound microbiomes from 100 DFU patients revealed that antibiotic therapy struggles to address the complex polymicrobial-multidrug-resistant pathological microenvironment. In contrast, debridement surgery promotes healing by dynamically modulating the wound microbiome to increase the proportion of commensal bacteria (Kalan et al., 2019). Therefore, enhancing healing may be achieved by dynamically regulating the DFU wound microbiome to augment beneficial bacteria while reducing pathogenic bacteria, rather than attempting to eliminate all bacterial species from the wound.

Nanoparticles (NPs), as a primary type of modern drug delivery system, are typically based on natural or synthetic materials and form spherical aggregates with drugs through non-covalent interactions. Their proven manufacturing technology and inherent therapeutic properties demonstrate significant potential in DFU treatment. On one hand, nanoparticles are prepared via simple, controllable processes suitable for large-scale production. On the other hand, the functionalities of specific materials—as the antimicrobial properties of silver nanoparticles (Tripathi and Goshisht, 2022), antioxidant effects of cerium oxide nanoparticles (Xu et al., 2023), and broad-spectrum bacteriostatic activity of ZnO nanoparticles (Zhang et al., 2021)—can precisely target the core pathologies of DFU wounds, including inflammation and oxidative stress, thereby achieving a “carrier-treatment” dual advantage.

However, it is not recommended as a stand-alone therapeutic agent due to dose toxicity issues (Lewinski et al., 2008). Recent studies have designed a drug delivery system encapsulating herbal active components that not only retains their therapeutic efficacy but also exerts synergistic effects (Ai et al., 2024). It was found that by encapsulating Resina Draconis extract, which has wound-healing and hemostatic effects, and Rhodiola rosea L. extract, which has antioxidant and anti-inflammatory effects, in novel silver composite nanoparticles (AgNPs) with antimicrobial properties. Compared with the control group, the addition of herbal medicines significantly shortened the inflammatory period by decreasing the levels of inflammatory factors, and promoted angiogenesis by inhibiting LPO and increasing VEGF levels. And the loading of AgNPs was confirmed to significantly promote wound epidermal remodeling and granulation tissue repair compared with different dressing groups. This study reveals that herbal active components based composite nanomaterials can synergistically promote wound healing (Ju et al., 2024b). In another study, aqueous extracts of Tagetes erecta L. and Portulaca oleracea L. were encapsulated in AgNPs and further mixed with a polyherbal gel formulation. This herbal gel achieved 85% wound closure in diabetic rats and further demonstrated that the combination of AgNP-multi-herbal active components enhances antimicrobial activity while promoting DFU repair (Shelar et al., 2025).

Nanoenzymes, with both nanomaterial properties and natural enzyme catalytic functions, are novel tools for regulating the microenvironment of DFUs. Nanoenzymes can play multiple synergistic roles in dealing with the complex pathological environment of DFUs: nanoenzymes with glucose oxidase (GOx) activity can break down glucose and improve the high-glucose environment (Liao et al., 2025); nanoenzymes mimicking catalase activity clear bacterial infections and inhibit wound microbial film formation (Zhao et al., 2023),Nanoenzymes with SOD- and CAT-like activities can reduce oxidative stress and improve wound ischemia and hypoxia by scavenging ROS (Xiao X. et al., 2024). Notably, the composite system of herbal active components and nano-enzymes can further realize the synergistic and synergistic effects of metabolic regulation and immunomodulation, providing a multidimensional intervention strategy for the treatment of DFUs.

In a recent study, metal-based nano-enzymes (MOFs) were combined with chlorogenic acid (CGA) extracted from Lonicera japonica Thunb and anchored in chitosan hydrogel to obtain a new type of nano-enzymatic hydrogel (MCGC). The results of the study showed that it could play a synergistic role, and the MOFs nano-enzyme and CGA released in the wound could play the catalytic activity of CAT-like enzyme to convert the accumulated H₂O₂ at the wound site into dissolved oxygen in the wound, alleviate the accumulation of ROS, and increase the oxygenation to promote wound healing. Moreover, CGA can clear the microbial membrane of the wound and reverse the bacterial infection of diabetic wounds (Wei et al., 2024). Another research group developed a novel delivery system for encapsulating astragalus polysaccharide (APS), an active ingredient of traditional Chinese medicine, in borax and iron-modified cerium nanoparticles (Fe/CeNP-PEG). It has been found that it can reduce inflammation by inhibiting the NLRP3/NF-κB signaling pathway, and animal experiments show that the healing rate can reach 97.6% (close to normal tissue). Moreover, the synergistic effect of APS and Fe/CeNP-PEG can dynamically regulate the microenvironment through antioxidant, anti-inflammatory, and pro-angiogenic effects, breaking through the limitations of traditional monotherapy (Zhang X. et al., 2025).

The latest breakthrough in treating DFUs is exosomes (MSCs-Exo) derived from mesenchymal stem cells (MSCs). One of the reasons for this is that MSCs have the ability to differentiate into a variety of cells that treat DFUs and secrete a variety of cytokines, growth factors, and chemokines that promote the healing of DFUs (Tienda-Vázquez et al., 2023; Wang H. et al., 2025).

Compared with MSC single-cell therapy, the proteins and signaling molecules on the surface of exosomes have strong targeting ability, which can transfer cytokines secreted by MSCs to target cells to regulate cell-to-cell signaling, promote immune response and tissue repair, and show multi-dimensional regulatory effects in wound healing (Bian et al., 2022; Sun et al., 2022). More importantly, adverse reactions such as immune rejection associated with transplantation of MSCs can be avoided (Wang H. et al., 2025). In recent years, studies on the combination of herbal active components and exosomes for wound healing in DFUs have gradually emerged. A recent study confirmed that pretreating mesenchymal stem cells (MSCs) with quercetin—a herbal active ingredient exhibiting anti-inflammatory and antioxidant properties—generated composite exosomes with significantly enhanced capacity to promote cell migration and ECM remodeling compared to untreated exosomes. Moreover, by 16S rRNA sequencing analysis, it was found that it could also play a role in promoting diabetic wound healing by regulating the intestinal microbiota (Wu et al., 2024). A recent study developed a novel vascular-targeting ginseng exosome loaded into a wireless biocompatible thermoelectric hydrogel. By mimicking endogenous electric field stimulation at wound sites, the system precisely controlled the release of pro-angiogenic ginseng exosomes, targeting electrophilic properties in epithelial and fibroblast cells to sustainably reverse endothelial dysfunction. Further experiments confirmed that this approach promoted tissue regeneration and revascularization in DFUs by activating the PPAR signaling pathway (Tan et al., 2025).

Currently, MSCs-Exo for the treatment of DFUs is still in the animal model stage. Several fatal problems still need to be solved for future clinical translation. Firstly, the issue of donor source needs strict regulation, which has failed to form a complete standardization and unification worldwide. Exosomes are under different regulatory models in different countries, in the United States exosomes are classified as drugs; in Europe and Japan, exosomes are classified as biologics (Wang H. et al., 2025). Secondly, as a new type of treatment, exosomes still need to be verified through more clinical trials in the future to see if they are effective in the long term and if there are potential side effects.

Advantages of hydrogels for developing tissue scaffolds in DFU healing lie in their structural and functional properties. First, they possess a hydrophilic polymer chain network with three-dimensional cross-linking, closely resembling the natural ECM. This structural mimicry enables effective drug loading and sustained release. Additionally, the hydrogel’s ECM-like environment provides an optimal microenvironment for cellular activities essential to wound repair (Choudhury et al., 2017; Güiza-Argüello et al., 2022). Importantly, the hydrogel is also transparent, allowing real-time monitoring of the complex pathology of DFUs at different stages (Wang X. et al., 2022). Additionally, hydrogels can stop bleeding by adhesion and create a long-term suitably moist local environment for the wound. Also conform to host wound tissue, which prevents excessive inflammatory response and thus protects the wound from infection (Shi et al., 2020; Liang et al., 2021; Gorain et al., 2022).

The combination of herbal active components with hydrogel can extend the action time of them and realize the advantages of “multi-target regulation-intelligent delivery-regulation of micro-environment-synergistic antimicrobial” with the help of advanced material properties of hydrogel. Zhang et al. prepared a composite hydrogel by loading Panax ginseng total saponin (PNS) on hyaluronic acid (HA)/carboxymethyl chitosan (CMCS). By establishing a skin wound model in type II diabetic SD rats, this hydrogel was found to significantly increase the wound healing rate in SD rats. The herbal hydrogel can not only reduce the inflammatory response of the body and reduce the expression of pro-inflammatory factors TNF-α and IL-6 but also enhance the expression of anti-inflammatory factor IL-10. It can also increase the expression of VEGF and play a role in promoting angiogenesis, which synergistically promotes the rapid healing of wounds (Zhang L. et al., 2023). Curcumin, possessing immunomodulatory and angiogenic properties, was formulated into a composite hydrogel. In vivo experiments demonstrated that this system not only scavenges ROS accumulation but also downregulates IL-1β expression while upregulating CD31 expression, thereby promoting angiogenesis and collagen deposition (Fan et al., 2024). In a recent study, a composite hydrogel with antimicrobial and antioxidant properties was made by ligating salvianolic acid B (SAB), which has anti-inflammatory properties and promotes local microcirculation, with Metal-polyphenol nanocomposite hydrogel. Its combined action synergistically promotes the healing of DFUs in an all-encompassing manner. On one hand, SAB and GOx act as anti-infective, microenvironmental modulators and pro-angiogenic agents, and on the other hand, they can also be released to improve mitochondrial energy metabolism through nanoparticles released in response to acidic wounding environments (Gong et al., 2025). Figure 3 summarizes the applications of active components of TCM in combination with novel delivery systems.