Mitochondria-mediated inflammation and diabetic wound healing: mechanisms and therapeutic strategies

Abstract

Diabetic wound (DW) healing impairment is one of the most common and serious complications of diabetes. DW is characterized by a complex pathogenesis involving hyperglycemia, oxidative stress, persistent inflammation, mitochondrial dysfunction, impaired angiogenesis, and neuropathy. Recent studies have revealed that mitochondria are not only the cellular powerhouses but also key organelles regulating inflammatory responses, redox balance, and cell fate. This review summarizes how mitochondrial dysfunction exacerbates inflammation and impedes the healing process in DW through mechanisms such as excessive reactive oxygen species (ROS) production, mitochondrial DNA (mtDNA) leakage, and aberrant inflammasome activation. Furthermore, it comprehensively outlines innovative therapeutic strategies targeting mitochondria, including mitochondria-specific antioxidants, metabolic reprogramming techniques, nanomaterial-based delivery systems, genetic engineering approaches, and natural product applications. These strategies are discussed from molecular mechanisms to clinical applications, aiming to provide new insights and a theoretical basis for the clinical management of DW. Systematic analysis indicates that therapeutic strategies targeting the mitochondria-inflammation axis hold significant potential and may represent a critical breakthrough in addressing the challenge of DW healing.

1. Introduction

Diabetic wound (DW) is one of the most prevalent and severe complications in diabetic patients, marked by high incidence, disability, and mortality rates. Globally, approximately 15%–25% of diabetic individuals will develop a foot ulcer during their lifetime, a significant proportion of which progress to chronic, non-healing wounds, leading to amputation or death (Cano Sanchez et al., 2018; Shao et al., 2025). Statistics indicate that the risk of lower extremity amputation is 15–40 times higher in diabetic patients compared to non-diabetics, with about one million patients undergoing amputation surgeries annually due to foot complications, imposing a heavy burden on patients, families, and healthcare systems (Senneville et al., 2024). Conventional treatments such as debridement, advanced dressings, negative pressure wound therapy, and hyperbaric oxygen therapy represent the current standard of care. However, despite these interventions, clinical outcomes remain suboptimal: approximately 30%–40% of diabetic foot ulcers fail to heal within 20 weeks of standard care, and the 5-year mortality rate following amputation exceeds 70% (Chen et al., 2024; Frykberg, 2021). Even when healing is achieved, recurrence rates approach 40% within 1 year, highlighting the urgent need for more effective therapeutic strategies that target the underlying molecular mechanisms.

The impairment of DW healing is a multifactorial, multi-stage pathological process involving hyperglycemia, accumulation of advanced glycation end products (AGEs), oxidative stress, persistent inflammation, impaired angiogenesis, neuropathy, and increased infection risk (Beegum et al., 2022; He et al., 2025). These factors interact, forming a vicious cycle that prevents normal healing. Conventional treatments such as debridement, dressing changes, negative pressure wound therapy, and hyperbaric oxygen therapy can alleviate symptoms but often fail to resolve the fundamental healing impairment (Chen et al., 2024; Frykberg, 2021). Recent molecular and cell biology research has highlighted the central role of mitochondrial dysfunction—characterized by membrane potential collapse, ETC., impairment, and excessive fission—in the initiation and progression of DW (Cano Sanchez et al., 2018). Mitochondrial dysfunction encompasses a spectrum of interrelated pathological alterations in mitochondrial structure and function. First, loss of mitochondrial membrane potential (ΔΨm) represents an early and critical event, as the proton gradient across the inner mitochondrial membrane is essential for ATP synthesis through oxidative phosphorylation. When ΔΨm dissipates, the driving force for ATP production is lost, and mitochondria may undergo permeability transition, releasing pro-apoptotic factors (Peng et al., 2023) (Table 1). Second, electron transport chain (ETC.) impairment involves dysfunction of complexes I-IV, leading to reduced electron transfer efficiency, decreased ATP generation, and increased electron leakage that promotes excessive reactive oxygen species (ROS) production (Guan et al., 2022). Third, cytochrome c release from the intermembrane space into the cytosol occurs when outer mitochondrial membrane integrity is compromised, triggering apoptotic cascades through apoptosome formation and caspase activation (Li JY. et al., 2024). Fourth, mitochondrial DNA (mtDNA) damage and leakage result from its proximity to ROS production sites and lack of protective histones, making it vulnerable to oxidative modifications that can be released as damage-associated molecular patterns (DAMPs) to activate inflammatory pathways (Zhao et al., 2021). Fifth, disrupted mitochondrial dynamics refers to imbalance between fission (mediated by Drp1) and fusion (mediated by Mfn1/2 and OPA1), leading to mitochondrial fragmentation and functional decline (Chen W. et al., 2023). Finally, impaired mitophagy compromises the selective autophagic clearance of damaged mitochondria, allowing dysfunctional organelles to accumulate and perpetuate oxidative stress and inflammation (Sulkshane et al., 2021). Mitochondria are not only the primary source of ATP but also participate in regulating apoptosis, calcium homeostasis, ROS generation, and immune responses (Cano Sanchez et al., 2018; Deng et al., 2023; Qi et al., 2024) (Table 1). Under hyperglycemic conditions, dysfunction of the mitochondrial electron transport chain (ETC.) leads to excessive ROS production, subsequently inducing oxidative damage, mitochondrial DNA (mtDNA) mutations/leakage, and activation of inflammatory pathways such as the NLR family pyrin domain containing 3 (NLRP3) inflammasome and the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING), thereby exacerbating local and systemic inflammation and hindering wound healing (Deng et al., 2023; Wang et al., 2025a; Öz and Çelik, 2016).

TABLE 1.

Mitochondrial alterations in diabetic wounds: Evidence from human and animal studies.

Mitochondrial function altered	Cell type/Tissue	Species/model	Key findings	References
Membrane potential (ΔΨm) ↓	Keratinocytes, fibroblasts	Human DW tissue; db/db mice	Significant ΔΨm reduction correlates with wound severity	Deng et al. (2023), Qi et al. (2024)
mtROS production↑	Endothelial cells, macrophages	Human dermal microvascular endothelial cells; STZ-induced diabetic rats	2–3 fold increase in mtROS; precedes inflammatory activation	Dai et al. (2024), Wang et al. (2022a)
ETC., complex dysfunction (Complex I, III)	Whole wound tissue	db/db mice; human DW biopsies	Reduced complex I and III activity; increased electron leakage	Guan et al. (2022), Akude et al. (2011)
mtDNA damage and leakage	Macrophages, keratinocytes	Human DW tissue; LPS-stimulated macrophages	8-oxo-dG levels elevated; cytosolic mtDNA detected	Deng et al. (2023), He et al. (2024)
Imbalanced fission/fusion (Drp1↑, Mfn2↓)	Endothelial cells	Human dermal microvascular endothelial cells; db/db mice	Drp1 phosphorylation increased; mitochondrial fragmentation	Qi et al. (2024), Kim et al. (2018b)
Impaired mitophagy (PINK1↓, Parkin↓)	Fibroblasts, keratinocytes	Human skin fibroblasts; STZ-induced diabetic rats	Reduced autophagic flux; accumulation of damaged mitochondria	Zhang et al. (2025b), Zhang et al. (2022)
ATP production↓	Whole wound tissue	db/db mice; human DW biopsies	40%–60% reduction in ATP content vs. healthy controls	Qi et al. (2024), Ding et al. (2025)
SOD2 activity↓	Mitochondrial fraction	Human DW tissue; OLETF rats	50%–70% reduction in MnSOD activity; increased oxidative damage	Li et al. (2022a), Trambas et al. (2025)

This article systematically reviews how mitochondrial dysfunction mediates inflammatory responses to affect DW healing, providing a comprehensive analysis from molecular mechanisms and cellular levels to overall pathophysiology. It also summarizes recent advances in therapeutic strategies targeting mitochondria, including pharmacological, genetic, cellular, and material-based approaches, to offer new perspectives and directions for future treatments.

2. Pathophysiological basis of DW healing

2.1. Normal wound healing process

Wound healing is a highly coordinated, dynamic process involving precise interactions among various cell types, cytokines, and extracellular matrix components. It can be divided into four overlapping yet distinct phases: hemostasis, inflammation, proliferation, and remodeling (Cano Sanchez et al., 2018; Beegum et al., 2022). The hemostatic phase begins immediately after injury, preventing further blood loss through platelet aggregation and coagulation system activation, and forming a provisional fibrin matrix that provides a scaffold for subsequent cell migration (Martin and Nunan, 2015; Renò et al., 2025). The inflammatory phase typically starts within hours post-injury and can last for several days, during which neutrophils and macrophages are recruited to the wound site to clear pathogens and necrotic tissue, while secreting various growth factors and cytokines to initiate repair (Peña and Martin, 2024; Farabi et al., 2024). The proliferation phase usually begins around days 3–4 post-injury and lasts 2–3 weeks, involving key processes such as fibroblast proliferation, collagen deposition, angiogenesis, and re-epithelialization. The remodeling phase is the longest, potentially lasting for months or years, and includes collagen reorganization and scar formation, ultimately restoring tissue integrity and function (Sideek et al., 2022; Bian et al., 2022; Guo and Dipietro, 2010). Various growth factors like PDGF, VEGF, EGF, and TGF-β play crucial roles in this process by activating specific signaling pathways that coordinate cellular activities, ensuring an orderly healing progression (Jian et al., 2022; Zhang et al., 2023; Hu et al., 2025; Ou et al., 2022) (Figure 1).

FIGURE 1.

Mechanisms by which hyperglycemia (HG) triggers mitochondrial dysfunction and subsequent inflammatory responses. Hyperglycemia enhances the mitochondrial tricarboxylic acid (TCA) cycle and increases electron (e⁻) leakage from the electron transport chain (ETC.), leading to elevated reactive oxygen species (ROS) production. Concurrently, reactions such as the Fenton reaction also promote ROS generation. On one hand, ROS degrades IκBα through mechanisms like phosphorylation, allowing NF-κB dimers to translocate into the nucleus and induce the transcription of inflammatory factors such as TNF-α, IL-6, and IL-1β. On the other hand, decreased mitochondrial membrane potential, cytochrome c (Cyt c) release, and damage-associated molecular patterns (DAMPs) including DNA fragments activate the NLRP3 inflammasome. This promotes the release of IL-1β and IL-18 and, via the cGAS-STING pathway, induces pyroptosis, ultimately sustaining the inflammatory state in diabetic chronic wounds. TCA tricarboxylic acid, ETC., electron transport chain, ROS reactive oxygen species, IκBα Inhibitor of Kappa B Alpha, NF-κB Nuclear Factor Kappa B, TNF-α Tumor Necrosis Factor-Alpha, IL-6 Interleukin-6, IL-1β Interleukin-1β, Cyt c Cytochrome c, DAMPs Damage-Associated Molecular Patterns, NLRP3 NLR Family Pyrin Domain Containing 3, IL-18 Interleukin-18, cGAS cyclic GMP-AMP Synthase, STING Stimulator of Interferon Genes.

2.2. Pathological features of DW

Compared to normal healing, DW exhibit delayed healing and significant pathological alterations. Key characteristics include a persistent inflammatory state, oxidative stress, impaired angiogenesis, abnormal cell function, disrupted extracellular matrix (ECM) remodeling, as well as neuropathy and infection risk. In DW, the inflammatory response is abnormally prolonged, with excessive M1 macrophage polarization and sustained high expression of inflammatory cytokines (Deng et al., 2023; Monteiro et al., 2022; Mahmoud et al., 2024). Normally, inflammation should subside within days, giving way to the proliferation phase; however, in the diabetic milieu, inflammatory signaling persists, hindering the progression of healing and exacerbating oxidative stress and cellular dysfunction (Elajaili et al., 2025). Oxidative stress may initiate the inflammatory response; DW exhibit excessive ROS production and compromised antioxidant enzyme systems. Hyperglycemia causes overworking of the mitochondrial, ETC., increased electron leakage, and substantial superoxide anion generation. Concurrently, AGEs interact with their receptors (RAGE), further increasing ROS production. Oxidative stress not only directly damages biomacromolecules but also activates multiple inflammatory pathways, creating a vicious cycle (Dai et al., 2024; Wang G. et al., 2022) (Table 1).

Furthermore, the diabetic environment leads to endothelial dysfunction and insufficient angiogenesis (Wang G. et al., 2022; He et al., 2024; Ding et al., 2025). Hyperglycemia and oxidative stress cause endothelial cell dysfunction, impair VEGF signaling, reduce nitric oxide (NO) bioavailability, and diminish angiogenic capacity. Basement membrane thickening and microangiopathy further restrict blood supply and oxygen delivery, causing tissue hypoxia and impeding healing. Key repair cells such as fibroblasts, keratinocytes, and endothelial cells exhibit functional impairments, with reduced migration and proliferation capacities (Huang et al., 2023). These cells display senescent characteristics, decreased responsiveness to growth factors, and arrested cell cycle progression, leading to delayed re-epithelialization and inadequate granulation tissue formation.

Disrupted ECM remodeling is another significant factor in DW pathology. Abnormal collagen deposition and an imbalance between matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) occur (Shao et al., 2025; Huang et al., 2023). DW show increased MMP expression and decreased TIMP expression, resulting in excessive ECM degradation and failure to form a stable scaffold supporting cell migration and tissue reconstruction. Additionally, diabetic neuropathy causes sensory loss, potentially preventing patients from detecting and addressing wounds promptly, thereby increasing infection risk. The hyperglycemic environment provides a favorable medium for bacterial growth, and compromised immune function further elevates infection susceptibility, forming another vicious cycle that impedes healing (Bragg et al., 2024).

3. Mitochondrial dysfunction and inflammation in the diabetic environment

3.1. Mitochondrial ROS and oxidative stress

Mitochondria-derived ROS play a pivotal role in initiating the cascade of DW healing impairment. Under normal conditions, mitochondria produce ATP via oxidative phosphorylation while generating small amounts of ROS as signaling molecules. Under physiological conditions, mitochondria regulate inner membrane fluidity and ROS production through complex III of the, ETC (Liang et al., 2025; McMinimy et al., 2024). However, this balance is profoundly disrupted in a hyperglycemic environment (Cao et al., 2012; Xu et al., 2024). High glucose levels increase tricarboxylic acid cycle intermediates, delivering excess electrons to the electron transport chain (ETC.). This, ETC., overload increases electron leakage and superoxide anion generation (Gerő et al., 2016; Akude et al., 2011); these superoxide anions can be converted to hydrogen peroxide by superoxide dismutase (SOD), and further react via the Fenton reaction to produce highly reactive hydroxyl radicals, causing severe oxidative damage (Dai et al., 2024; Xu Z. et al., 2022; Thomas et al., 2009), this is the main source of mitochondrial reactive oxygen species (mtROS). Excessive ROS not only directly oxidatively damage mtDNA, leading to mutations and deletions, but also induce mitochondrial membrane lipid peroxidation and protein functional inactivation, triggering decreased mitochondrial membrane potential and cytochrome C release (Zhen et al., 2023; Mendoza et al., 2024; Wu et al., 2019; Feng et al., 2022) (Table 1).

The cellular antioxidant defense system, comprising both enzymatic and non-enzymatic components, normally maintains redox homeostasis. The four primary antioxidant enzymes include: superoxide dismutase (SOD), which catalyzes the dismutation of superoxide anions (O₂ ⁻) to hydrogen peroxide (H₂O₂) and oxygen; catalase (CAT), which converts H₂O₂ to water and oxygen; glutathione peroxidase (GPx), which reduces H₂O₂ and organic hydroperoxides using reduced glutathione (GSH) as a cofactor; and glutathione reductase (GR), which regenerates GSH from oxidized glutathione (GSSG) using NADPH (Jomova et al., 2024; Djordjević et al., 2022). Of particular relevance to mitochondrial function, SOD2 (manganese-containing SOD, MnSOD) is localized exclusively in the mitochondrial matrix and represents the first line of defense against mitochondrially-derived superoxide, whereas SOD1 (copper-zinc-containing SOD, Cu/ZnSOD) is primarily cytosolic but also present in the mitochondrial intermembrane space (N and aziroğlu, 2007; Cui et al., 2024). In diabetic conditions, SOD2 expression and activity are often downregulated, compromising the mitochondrial antioxidant capacity and exacerbating mtROS accumulation (Li Q. et al., 2022; Trambas et al., 2025) (Table 1). Studies show significantly elevated ROS levels and decreased antioxidant defense system function in DW tissues. The activities of antioxidant enzymes including SOD (particularly SOD2), CAT, GPx, and GR are markedly reduced, while oxidative stress markers such as malondialdehyde (MDA) and protein carbonylation levels are significantly increased (Qian et al., 2021; Akter et al., 2025; Xie et al., 2019). This disruption of redox balance not only directly damages cellular structures and macromolecules but also serves as the fundamental trigger for activating the inflammatory pathways, ultimately exacerbating tissue damage (Wang G. et al., 2022; Tian et al., 2024; He et al., 2021; Jha et al., 2022) (Figure 2A).

FIGURE 2.

Impact of mitochondria-related mechanisms on wound healing in the diabetic environment. (A) Under hyperglycemia (HG), mitochondria generate ATP. While antioxidants can suppress ROS, levels of MDA, protein carbonyls (C=O), etc., increase, and changes occur in enzymes like SOD, CAT, and GPX, triggering cell damage, inflammation, and apoptosis, ultimately affecting tissue repair. (B) Mitochondria produce ROS, and released mitochondrial DNA (mtDNA) fragments are recognized by cGAS, activating STING and TBK1, leading to IRF3 nuclear translocation and induction of type I interferon (IFN-I)-related inflammation, hindering diabetic wound healing. (C) Hyperglycemia acts on mitochondria through proteins like DRP1. Involving GTPase activity and other processes, changes related to mitochondrial fission and the mitochondrial permeability transition pore (mPTP) occur, resulting in decreased ATP production, reduced membrane potential (ΔΨm), and increased ROS, leading to apoptosis and impaired diabetic wound healing. (D) Hyperglycemia causes a decrease in mitochondrial membrane potential. Mediated by PINK1, Parkin, and involving OPTN and NDP52, mitophagy is affected. This subsequently exacerbates inflammation through ROS, mtDNA, etc., promoting cell death and senescence, which is detrimental to diabetic wound healing. HG HyperGlycemia, ATP Adenosine Triphosphate, ROS reactive oxygen species, MDA Malondialdehyde, SOD Superoxide Dismutase, CAT Catalase, GPX Glutathione Peroxidase, mtDNA mitochondrial DNA, cGAS cyclic GMP-AMP Synthase, STING Stimulator of Interferon Genes, TBK1 TANK-Binding Kinase 1, IRF3 Interferon Regulatory Factor 3, IFN-I type I interferon, DRP1 Dynamin-related protein 1, GTP Guanosine Triphosphate, mPTP mitochondrial Permeability Transition Pore, ΔΨm Mitochondrial Membrane Potential, PINK1 PTEN-induced Kinase 1, OPTN Optineurin, NDP52 Nuclear dot protein 52.

3.2. Inflammatory pathway activation via mtROS and mtDNA leakage

3.2.1. mtROS and the NLRP3 inflammasome

mtROS is a potent activator of the NLRP3 inflammasome, a multiprotein platform composed of NLRP3, ASC, and caspase-1 (Jang et al., 2015; Wang et al., 2024). Mitochondrial dysfunction plays a critical role in activating this pathway. Specifically, mtROS is believed to induce the dissociation of thioredoxin-interacting protein (TXNIP) from thioredoxin; TXNIP then directly binds to and activates the NLRP3 inflammasome (Zhou et al., 2010; Zhang et al., 2024). Recent studies suggest this process may be associated with mitochondrial iron accumulation (Ar et al., 2025). Furthermore, the mitochondrial, ETC., can also sustain NLRP3 inflammasome activation through non-ROS-dependent pathways, such as via phosphocreatine (PCr)-dependent ATP generation (Billingham et al., 2022). However, the central role of mtROS in NLRP3 activation remains contentious. Some studies have challenged this view, suggesting that inhibiting mtROS and mitochondrial function using high concentrations of chemical inhibitors can easily produce experimental artifacts (Muñoz-Planillo et al., 2013; Bauernfeind et al., 2011). These conflicting findings indicate that the role of mtROS may be influenced by experimental conditions. For instance, some research points out that under certain inhibitor treatments, ROS scavenging might concurrently interfere with the “priming signal” necessary for NLRP3 activation, thereby complicating the interpretation of results (Bauernfeind et al., 2011). Consequently, although substantial evidence supports the central importance of mtROS, its precise role and necessary conditions remain a forefront topic of intense investigation in the field. Activated caspase-1 then cleaves pro-IL-1β and pro-IL-18 into their bioactive forms, IL-1β and IL-18, which are released extracellularly, strongly amplifying local and systemic inflammatory responses (Liu et al., 2022; Ding et al., 2022). The activation level of the NLRP3 inflammasome is significantly higher in DW tissues compared to normal tissues and is closely associated with indicators of mitochondrial dysfunction (Wang et al., 2025a; He et al., 2024; Sun et al., 2023) (Figure 1).

3.2.2. NF-κB pathway

Nuclear factor kappa B (NF-κB) is a master transcription factor regulating inflammatory responses (Vringer et al., 2024). In its resting state, NF-κB is bound to its inhibitory protein inhibitor of kappa b alpha (IκBα) in the cytoplasm. ROS can oxidatively modify regulatory subunits of the IκB kinase (IKK) complex, promoting IκBα phosphorylation and subsequent degradation via the ubiquitin-proteasome pathway, thereby releasing active NF-κB dimers (e.g., p50-p65) for nuclear translocation (Sá-Pessoa et al., 2023; Kim JY. et al., 2018). Within the nucleus, NF-κB binds to specific gene promoter regions, initiating the transcription of key pro-inflammatory cytokines such as tumor necrosis factor-alpha (TNF-α), IL-6, and IL-1β (Hu et al., 2020). Multiple studies confirm that in the DW microenvironment, persistent hyperglycemia-induced excessive mitochondrial ROS production leads to sustained activation of the NF-κB signaling pathway, creating a pro-inflammatory positive feedback loop that hinders the wound healing process (Wang G. et al., 2022; Tian et al., 2024) (Figure 1).

3.2.3. Cytosolic mtDNA and the cGAS-STING pathway

mtDNA is particularly vulnerable to oxidative damage due to its lack of histone protection and proximity to ROS generation sites (Hayakawa et al., 1992; Barja and Herrero, 2000). The oxidative stress causes mtDNA damage and compromises mitochondrial membrane integrity, allowing mtDNA to leak into the cytosol (Wang et al., 2025a; He et al., 2024) (Table 1). This cytosolic mtDNA is recognized as a damage-associated molecular pattern (DAMP) (Zhou et al., 2011; Yu et al., 2014). It can be sensed by cyclic GMP-AMP synthase (cGAS), activating the stimulator of interferon genes (STING) pathway. Activated STING recruits TBK1, which phosphorylates IRF3, promoting the expression of type I interferons and other inflammatory cytokines (Wang et al., 2025a; He et al., 2024). It is noteworthy that in diabetic wound models using C57 mice, while the cGAS-STING pathway in macrophages becomes pathogenic due to chronic excessive activation caused by persistent mitochondrial DNA leakage (Geng et al., 2021), it may also serve as an important innate immune surveillance mechanism in skin tissue under physiological conditions. However, in some C57 mouse skin wound models, including diabetic wounds, this pathway becomes dysregulated in macrophages or endothelial cells, shifting the balance toward a chronic inflammatory state (Li F. et al., 2024; Geng et al., 2023; Chen Y. et al., 2023; Koo et al., 2019; Zhang S. et al., 2025) (Figure 2B).

3.3. Disruption of mitochondrial dynamics and quality control

3.3.1. Imbalanced mitochondrial fission and fusion

Mitochondria are dynamic organelles that maintain network homeostasis through continuous fission and fusion (Chan, 2020; Quintana-Cabrera and Scorrano, 2023). Mitochondrial fission is mediated by Drp1, while fusion is regulated by Mfn1/2 and OPA1 (Tang et al., 2024; Kim YM. et al., 2018; Sidarala et al., 2022; Liu et al., 2021). In diabetes, this balance is disrupted, shifting towards excessive fission and resulting in mitochondrial fragmentation and functional impairment (Sun et al., 2021). At the molecular level, the mechanisms governing fission and fusion are precisely regulated. PDIA1 binds to Drp1 to reduce its redox state. Loss of PDIA1 increases sulfenylation of Drp1 at Cys644 and enhances Drp1 activity, promoting mitochondrial fragmentation and mtROS production, which ultimately leads to endothelial cell dysfunction (Kim YM. et al., 2018) (Table 1). On the fusion side, Mfn1 and Mfn2 are essential for glucose-stimulated insulin secretion (GSIS) primarily by regulating mitochondrial DNA (mtDNA) content. Combined deletion of Mfn1/2 in β-cells reduces mtDNA content, impairs mitochondrial morphology and network, and compromises respiratory function, eventually resulting in severe glucose intolerance (Sidarala et al., 2022). Furthermore, CK2α-mediated Jak2-Stat3 phosphorylation activates the transcription of Opa1, thereby promoting mitochondrial fusion and suppressing mitochondrial oxidative stress (Liu et al., 2021). These mechanisms represent promising targets for overcoming mitochondrial dysfunction in diabetes and restoring glycemic control. Fragmented mitochondria are functionally deficient, producing less ATP and more ROS, and exhibit a decreased membrane potential, further promoting apoptosis (Qi et al., 2024; Sun et al., 2021). Research finds this abnormal fragmented morphology and reduced ATP output in DW tissues, failing to meet the energy demands for repair and proliferation (Deng et al., 2023; Qi et al., 2024) (Table 1). This disruption also impairs mitochondrial quality control, as fragmented mitochondria may evade autophagic clearance, accumulating and continuously generating ROS and inflammatory signals (Wang et al., 2025a) (Figure 2C).

3.3.2. Mitophagy impairment

Mitophagy is a crucial quality control mechanism for selectively removing damaged mitochondria, essential for maintaining a healthy mitochondrial network (Bharath et al., 2020; Li A. et al., 2022), primarily mediated by the PINK1-Parkin pathway (Narendra and Youle, 2024; Lazarou et al., 2015; Lin et al., 2019). When mitochondrial membrane potential declines, PINK1 stabilizes on the outer mitochondrial membrane, recruiting and activating the E3 ubiquitin ligase Parkin (Table 1). Parkin then ubiquitinates outer mitochondrial membrane proteins, recruiting autophagy receptors like OPTN and NDP52, ultimately leading to the engulfment and degradation of damaged mitochondria by autophagosomes (Zhang C. et al., 2025; Wang et al., 2025b; Zhang et al., 2022) (Figure 2D).

In the diabetic environment, mitophagy is impaired, leading to the accumulation of dysfunctional mitochondria. Studies show downregulated PINK1 and Parkin expression and obstructed autophagic flux in DW tissues (Zhang C. et al., 2025). Dysfunctional mitochondria continuously produce ROS and leak mtDNA, further activating inflammatory pathways and forming a vicious cycle (Wang et al., 2025a). Mitophagy impairment also affects cell fate decisions. During wound healing, moderate autophagy is necessary for cells to adapt to stressful environments and clear damaged components. However, in diabetes, disrupted autophagy may lead to aberrant cell death or senescence, hindering tissue repair (Wang et al., 2025a; Ding et al., 2025) (Figure 2D) (Table 1).

4. Central role of the mitochondria-inflammation axis in DW

4.1. Macrophage polarization and mitochondrial metabolism

Macrophages play a dual role in wound healing, and their phenotypic polarization directly influences the healing outcome (Fu et al., 2023). Typically, macrophages are categorized into classically activated M1 (pro-inflammatory) and alternatively activated M2 (anti-inflammatory/pro-repair) types (Chen Z. et al., 2023). In normal wound healing, M1 macrophages dominate the early phase, clearing pathogens and necrotic tissue (Louiselle et al., 2021), later shifting towards the M2 phenotype to promote tissue repair and angiogenesis (Zhou et al., 2023). However, in DW, macrophage polarization is arrested in the M1 state, leading to chronic inflammation and impaired healing (Shao et al., 2025; Deng et al., 2023; Monteiro et al., 2022). Mitochondrial metabolism plays a key role in macrophage polarization. M1 macrophages primarily rely on glycolysis for energy, exhibit increased mitochondrial ROS production and succinate accumulation, promoting Hypoxia-Inducible Factor-1α (HIF-1α) stabilization and inflammatory gene expression. In contrast, M2 macrophages depend on oxidative phosphorylation (OXPHOS) and possess intact mitochondrial function and fatty acid oxidation capacity (Shao et al., 2025; Monteiro et al., 2022). Notably, the hyperglycemic and high-AGE microenvironment within the DW vasculature and surrounding tissue actively reinforces and sustains the pro-inflammatory M1 macrophage phenotype through multiple interconnected mechanisms (Fu et al., 2023). firstly, the accumulation of AGEs engages their receptor RAGE on macrophages, initiating robust pro-inflammatory signaling cascades such as the NF-κB pathway, which transcriptionally upregulates key M1 markers (e.g., TNF-α, IL-6, iNOS) while suppressing M2-associated genes like Arg1 (Dong et al., 2016; Yu et al., 2025). Secondly, hyperglycemia-driven mitochondrial dysfunction promotes the accumulation of the TCA cycle intermediate succinate, which inhibits prolyl hydroxylases (PHDs) and stabilizes HIF-1α, a master transcriptional regulator that enhances the expression of IL-1β and other M1-associated inflammatory mediators, creating a feed-forward inflammatory loop (Tannahill et al., 2013; Fuhrmann et al., 2019). Furthermore, the high-glucose environment exacerbates mtROS production, which acts as a potent signaling molecule to directly activate the NLRP3 inflammasome, thereby further cementing the M1 transcriptional program (Xu et al., 2025; Geng et al., 2024). Beyond mtROS, other danger signals including ATP, crystalline substances, and membrane damage also contribute to NLRP3 activation in the hyperglycemic, AGE-rich, and oxidative DW microenvironment (Deng et al., 2023; Wang et al., 2025a). Once activated, NLRP3 inflammasome components drive sustained IL-1β and IL-18 release, which recruit and activate neutrophils and monocytes while IL-1β promotes vascular permeability and leukocyte infiltration, and IL-18 enhances IFN-γ production—together forming an inflammatory amplification loop that perpetuates chronic inflammation and obstructs healing (Wang et al., 2025a) (Figure 3). Collectively, the synergistic action of AGE-RAGE signaling, metabolic rewiring, and oxidative stress in the DW microenvironment creates a powerful, self-reinforcing circuit that locks macrophages into a persistent M1 state, thereby perpetuating chronic inflammation and impeding the resolution of healing (Figure 3).

FIGURE 3.

Integrated schematic of mitochondrial dysfunction as a central mechanism impairing diabetic wound healing and targeted therapeutic strategies. The figure delineates a cohesive pathological cascade from the diabetic microenvironment to failed tissue repair. The process originates from the diabetic microenvironment, characterized by hyperglycemia and accumulation of advanced glycation end products (AGEs). These factors converge to induce core damage: mitochondrial dysfunction, encompassing impaired mitochondrial dynamics, mitophagy, and electron transport chain function. This dysfunction results in metabolite accumulation (e.g., succinate) and excessive mitochondrial reactive oxygen species (mtROS) production. These primary disturbances activate two key downstream pathways: 1) NLRP3 inflammasome activation, and 2) dysregulated macrophage polarization, characterized by a sustained pro-inflammatory M1 phenotype. Together, these pathways drive a state of persistent chronic inflammation, which disrupts the balance between pro-inflammatory cytokines (e.g., IL-1β, TNF-α) and pro-repair growth factors (e.g., VEGF, TGF-β). The consequent cellular dysfunction, senescence/apoptosis, and impaired angiogenesis collectively lead to the final result: failure of tissue repair and wound healing. Abbreviations: AGEs, Advanced glycation end products; mtROS, mitochondrial reactive oxygen species; NLRP3, NLR family pyrin domain containing 3; IL-1β, Interleukin-1β; TNF-α, Tumor necrosis factor-alpha; VEGF, Vascular endothelial growth factor; TGF-β, Transforming growth factor-beta; GLP-1 RAs, Glucagon-like peptide-1 receptor agonists.

The diabetic environment, characterized by hyperglycemia and oxidative stress, disrupts mitochondrial function, promoting polarization towards the M1 phenotype (Luo et al., 2023; Nedosugova et al., 2022). Studies find increased expression of M1 macrophage markers and decreased expression of M2 markers in DW. Specifically, the macrophage population in DW has undergone significant changes. Compared to acute wounds, the number of M1 macrophages has increased by 2-3 fold, while M2 macrophages have decreased by approximately 50%–60%, as determined by flow cytometry and immunohistochemical analysis of wound biopsies (Deng et al., 2023; Fu et al., 2023). This polarization imbalance is reflected not only in marker expression (increased iNOS, CD86; decreased Arg1, CD206) but also in absolute cell counts, which not only maintains a chronic inflammatory state but also suppresses angiogenesis and extracellular matrix (ECM) remodeling (Shao et al., 2025; Deng et al., 2023). Modulating macrophage metabolic reprogramming has become a new therapeutic strategy. Research shows that promoting M2 polarization by upregulating arginase and downregulating inducible nitric oxide synthase, and correcting succinate dehydrogenase (SDH) in OXPHOS and the TCA cycle, can reduce inflammation (Zhao et al., 2022). Similarly, injectable hydrogels inhibiting SDH activity, reducing ROS, and promoting M2 macrophage conversion significantly improve DW healing (Shao et al., 2025). Leptin also enhances the action of IL-4 in macrophages, leading to increased oxygen consumption, upregulation of macrophage markers associated with a tissue-repair phenotype, and promotion of wound healing (Shao et al., 2025). Furthermore, a more critical perspective on the failed M2 shift reveals that it is not solely a consequence of being overwhelmed by persistent inflammatory signals. A fundamental defect in the M2-polarization program itself exists, rooted in the diabetes-induced mitochondrial damage that cripples the specific bioenergetic infrastructure required for alternative activation. Specifically, the efficient execution of fatty acid oxidation (FAO) and oxidative phosphorylation (OXPHOS)—the core metabolic pathways fueling the M2 phenotype—is severely compromised in the diabetic milieu (Purvis et al., 2024; He et al., 2019). Persistent mitochondrial dysfunction, directly undermines the cell’s capacity for OXPHOS. As demonstrated by reduced oxygen consumption rate (OCR), decreased basal and maximal respiration, and lower ATP-linked respiration in macrophages exposed to diabetic conditions (Wang L. et al., 2022; Xu L. et al., 2022). Furthermore, FAO capacity, measured by palmitate-stimulated OCR and expression of FAO enzymes (CPT1a, ACADL), is significantly impaired, preventing the metabolic reprogramming required for M2 activation (Liu et al., 2023). Consequently, even in the presence of M2-polarizing cues like IL-4, macrophages lack the functional metabolic machinery to initiate and sustain the FAO-OXPHOS metabolic program (Van den Bossche et al., 2015). This creates a dual barrier to M2 polarization: an actively hostile signaling environment that promotes M1, and a passive bioenergetic failure that prevents the cell from responding to pro-repair signals. Therefore, the failure of the M2 shift is a synergistic outcome of both sustained pro-inflammatory drivers and an intrinsic inability to utilize the specific metabolic fuels necessary for the anti-inflammatory and pro-repair functions of M2 macrophages (Figure 3).

4.2. Endothelial cell dysfunction

Endothelial cells play a central role in angiogenesis and maintaining vascular integrity. In diabetes, endothelial cell function is severely compromised, manifesting as decreased proliferation/migration, increased apoptosis, and impaired angiogenic capacity. Mitochondrial dysfunction plays a key role in this process (Wang G. et al., 2022; He et al., 2024; Ding et al., 2025). Fibroblasts, the primary cells responsible for ECM production and remodeling, are similarly affected by mitochondrial dysfunction in the diabetic environment. Diabetic fibroblasts exhibit mitochondrial fragmentation, reduced ATP production, and increased mtROS generation, leading to senescence and decreased proliferative capacity (Huang et al., 2023) (Zhang C. et al., 2025). This results in reduced collagen synthesis (particularly collagen type I and III) and an altered ratio of MMPs to TIMPs, favoring excessive ECM degradation (Huang et al., 2023) (Shao et al., 2025). The impaired cross-talk between dysfunctional endothelial cells and fibroblasts further compromises angiogenesis, as endothelial cells provide critical paracrine signals (such as PDGF-BB) that recruit and activate fibroblasts, while fibroblasts produce VEGF and deposit the ECM scaffold necessary for endothelial tube formation. This bidirectional dysfunction creates a self-perpetuating cycle of impaired vascularization and matrix dysregulation that severely compromises wound healing (Yang et al., 2020; Xie et al., 2013). Hyperglycemia leads to increased mitochondrial ROS production in endothelial cells, exacerbating oxidative stress. mtROS can directly damage endothelial cell DNA, proteins, and lipids, promoting senescence and apoptosis. Furthermore, mtROS can oxidize tetrahydrobiopterin (BH4), causing endothelial Nitric Oxide Synthase (eNOS) uncoupling–where eNOS produces superoxide anions instead of NO–further increasing oxidative stress and reducing NO bioavailability (Wang G. et al., 2022; Ding et al., 2025). NO is a key mediator of vasodilation and angiogenesis. Reduced NO bioavailability in diabetes leads to impaired vasodilation and angiogenesis. Concurrently, oxidative stress activates inflammatory pathways like NF-κB, promoting the expression of inflammatory cytokines and further damaging endothelial function (Wang G. et al., 2022; Ding et al., 2025) (Figure 3).

Endothelial progenitor cells (EPCs) are important for vascular repair, mobilizing from the bone marrow to the wound site to participate in neovascularization. However, diabetic patients have reduced EPC numbers and impaired function. Studies show that diabetic EPCs exhibit mitochondrial dysfunction, increased ROS production, and decreased migration and tube-forming capacity (Ding et al., 2025).

5. Therapeutic strategies targeting mitochondria

Given the central role of mitochondrial dysfunction in the pathogenesis of DW, developing therapeutic strategies that directly target mitochondria has become a key research focus. These approaches aim to restore mitochondrial homeostasis, correct the metabolic-inflammatory axis imbalance, and thereby promote wound healing.

5.1. Mitochondria-targeted antioxidants and metabolic modulators

Many natural compounds exert their therapeutic effects by improving mitochondrial function. Curcumin, at doses that achieve a hormetic effect (e.g., 10 mg/L or approximately 28 μM in vitro), can enhance antioxidant defense by activating the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway, upregulating glutathione (GSH) metabolism, and inducing glutathione S-transferase (GST) activity, particularly isoforms involved in detoxifying lipid peroxidation products such as 4-hydroxynonenal (4-HNE); it also inhibits NF-κB-mediated inflammation (Bayet-Robert and Morvan, 2013; Piper et al., 1998) (Table 2). It is important to note that curcumin exhibits a biphasic dose-response relationship: lower doses activate protective pathways—including increased total glutathione (GSx) and GST activity—while higher doses deplete GSH, reduce related metabolites (e.g., taurine, homocysteine), and may induce pro-oxidant effects or cellular toxicity (Bayet-Robert and Morvan, 2013; Ali and Rattan, 2006). This hormetic phenomenon, where low to moderate doses stimulate adaptive protective responses and high doses become detrimental, is characteristic of many phytochemicals and must be carefully considered in therapeutic applications (Gong et al., 2023; Scharstuhl et al., 2009). Resveratrol, a natural activator of SIRT1, can deacetylate and activate key transcription factors, reducing oxidative stress and promoting mitophagy (Ciccone et al., 2022) (Table 2). These natural products function as multi-target modulators of mitochondrial health. From a genetic and cellular perspective, enhancing mitochondrial quality control is a fundamental strategy. This includes employing mitochondrial-targeted peptides and exploring gene therapies aimed at correcting defective mitophagy (e.g., via the PINK1-Parkin pathway) or normalizing imbalanced mitochondrial dynamics (Deng et al., 2023; Wang et al., 2025a; Zhang C. et al., 2025) (Tables 1, 2).

TABLE 2.

Therapeutic strategies targeting mitochondria in diabetic wound healing.

Therapeutic strategy	Mechanism/target	Effect on wound healing	Effective model/cell type	References
MitoQ (Mitoquinone)	Mitochondria-targeted antioxidant; scavenges mtROS (Single target: mtROS)	35%–40% faster wound closure; improved re-epithelialization	Diabetic mouse wound model; Endothelial cells	Xiao et al. (2017), Zhao et al. (2019)
Elamipretide (SS-31)	Binds cardiolipin, stabilizes, ETC., reduces ROS (Single target: ETC., integrity)	Reduced wound area by 45%; decreased inflammatory markers	Diabetic mouse wound model; Macrophages	Zhao et al. (2019)
Dimethyl Malonate (DMM) hydrogel	Inhibits SDH, reduces succinate, promotes M2 polarization (Multi-target: metabolism + inflammation)	50% accelerated healing; increased M2/M1 ratio	Diabetic rat wound model; Macrophages	Shao et al. (2025), Liu et al. (2025)
CeO2@Tau@Hydrogel@Microneedle (CTH@MN)	Taurine-mediated anti-senescence + CeO2 mtROS scavenging; inhibits ROS/NF-κB pathway and activates autophagy (Multi-target: oxidative stress + inflammation + senescence)	Significantly reduced wound area; attenuated oxidative damage; decreased inflammatory cytokines; counteracted cellular senescence; promoted pro-regenerative immune microenvironment	Significantly reduced wound area; attenuated oxidative damage; decreased inflammatory cytokines; counteracted cellular senescence; promoted pro-regenerative immune microenvironment	Tian et al. (2024), Singh et al. (2023), Koo et al. (2023)
Mesoporous polydopamine NPs + SS-31	Photothermal antibacterial + mitochondrial protection (Multi-target: bacteria + mitochondria)	40% faster wound closure; enhanced re-epithelialization and collagen deposition	Diabetic mouse full-thickness wound model	Cano Sanchez et al. (2018), Deng et al. (2023)
Zn/C-dots nanozymes	SOD/CAT-like activity, scavenges ROS (Multi-target: ROS + bacteria)	Reduced wound area, bacterial load, and inflammatory cytokines	Diabetic mouse wound model	Dai et al. (2024)
Curcumin	Activates Nrf2, inhibits NF-κB (Multi-target: antioxidant + anti-inflammatory)	Improved wound healing parameters	In vitro endothelial cells; Diabetic rat model	Gong et al. (2023), Scharstuhl et al. (2009)
Resveratrol	Activates SIRT1, promotes mitophagy (Multi-target: autophagy + oxidative stress)	Enhanced wound closure	In vitro endothelial cells; Diabetic mouse model	Ciccone et al. (2022)
PINK1-Parkin pathway enhancers	Promotes mitophagy, clears damaged mitochondria (Single target: mitophagy)	35% improved wound closure; restored mitophagic flux	Diabetic mouse wound model; Keratinocytes	Zhang et al. (2025b), Wang et al. (2025b), Zhang et al. (2022)
MSC-EVs (Extracellular Vesicles)	Mitochondrial transfer, restores bioenergetics, inhibits NETs (Multi-target: energy + inflammation + angiogenesis)	Accelerated wound healing; inhibited NET-induced endothelial ferroptosis	Diabetic mouse wound model; Neutrophils, Endothelial cells	Ding et al. (2025), Lu et al. (2024)
WOC nanoplatform	Promotes M2 mitochondrial transfer to endothelial cells (Multi-target: macrophage polarization + angiogenesis)	Restored vascular function; accelerated wound healing	Diabetic mouse wound model; Macrophages, Endothelial cells	Dai et al. (2024), He et al. (2024), Qin et al. (2025), Huang et al. (2025)

Recent advances highlight several mitochondria-targeted therapeutic strategies for diabetic wound repair. The CTH@MN system (CeO₂@Tau@Hydrogel@Microneedle) leverages taurine’s anti-senescence properties and cerium oxide’s potent mtROS-scavenging ability to inhibit the ROS/NF-κB pathway and activate autophagy (Table 2). This dual action attenuates oxidative damage and inflammation while countering cellular senescence, creating a pro-regenerative immune microenvironment that targets the “oxidation-inflammation-aging” pathological axis (Tian et al., 2024; Singh et al., 2023; Koo et al., 2023). Another emerging strategy targets mitochondrial-derived vesicles (MDVs). Under hyperglycemic conditions, upregulation of sorting nexin 9 (SNX9) triggers abnormal MDV production, transferring damaged mitochondrial components to recipient cells and impairing wound healing. Inhibiting SNX9 blocks harmful MDV formation, restores mitochondrial dynamics, and rescues healing in diabetic mice, positioning MDVs as promising therapeutic targets (Zhang H. et al., 2025). Additionally, Histatin 1 (Hst1) from human saliva accelerates wound healing by regulating mitochondria-associated endoplasmic reticulum membranes (MAMs). Hst1 inhibits the IP3R1/GRP75/VDAC1 complex, reducing MAM assembly and preventing mitochondrial calcium overload, while simultaneously inducing ERK-mediated Nrf2 nuclear translocation to enhance antioxidant defenses. This reverses endothelial cell senescence and promotes angiogenesis via the MAM-mediated mitochondria-senescence axis (Xian et al., 2024).

Conventional antioxidants are limited by poor mitochondrial specificity, but mitochondria-targeted compounds offer greater potential (Deng et al., 2023; Xiao et al., 2017). SS31 is a mitochondria-targeted peptide that specifically binds to cardiolipin, a phospholipid found exclusively on the inner mitochondrial membrane and essential for cristae formation (Chavez et al., 2020; Szeto, 2014). Through electrostatic and hydrophobic interactions with cardiolipin, SS31 prevents the oxidation of both cardiolipin and cytochrome C while disrupting their interaction (Szeto and Birk, 2014; Sweetwyne et al., 2017; Liu et al., 2019). This stabilizes the electron transport chain, enhancing electron transfer and oxidative phosphorylation, thereby reducing mitochondrial reactive oxygen species (mtROS) production and boosting ATP synthesis (Sweetwyne et al., 2017; Birk et al., 2013). The consequent decrease in mtROS and increase in ATP availability promote the polarization of macrophages toward the anti-inflammatory M2 phenotype. This shift upregulates the secretion of growth factors such as vascular endothelial growth factor (VEGF) and epidermal growth factor (EGF), ultimately enhancing cellular adhesion, proliferation, and migration (Burnstock et al., 2012; Li et al., 2019). MitoQ primarily localizes to the mitochondrial matrix, where it efficiently scavenges mtROS. Meanwhile, elamipretide acts by binding to cardiolipin, stabilizing the, ETC., supercomplexes, and reducing electron leakage, thereby decreasing mtROS production at its source (Deng et al., 2023; Zhao et al., 2019) (Table 2). While MitoQ has been shown to accumulate in mitochondrial membranes and prevent ROS accumulation in multiple tissues in vivo, its effects can be tissue-specific. For instance, studies indicate that mice fed a high-fat diet and treated with MitoQ exhibit minimal metabolic benefits in adipose tissue itself, despite significant improvements in systemic metabolism (Bond et al., 2019). Beyond direct antioxidant strategies, metabolic reprogramming offers a promising approach to address the underlying energy crisis in diabetic wounds (DW). For example, inhibiting succinate dehydrogenase (SDH) activity with dimethyl malonate (DMM) delivered via injectable hydrogels has been shown to reduce succinate accumulation (Table 2). This alleviates HIF-1α-mediated inflammation and promotes the repolarization of macrophages toward the M2 phenotype (Shao et al., 2025), demonstrating that correcting specific mitochondrial metabolic pathways is a viable therapeutic strategy (Liu et al., 2025) (Table 2). Moreover, inhibiting NLRP3 inflammasome activation has become an important therapeutic strategy. Studies show that using NLRP3 inhibitors or interventions targeting upstream activation signals can significantly reduce inflammation and improve wound healing. For instance, mitochondria-targeted antioxidants can reduce mtROS production, indirectly suppressing NLRP3 inflammasome activation (Deng et al., 2023) (Figure 3). Research indicates that antioxidant therapy, metabolic modulation, or enhanced mitophagy can improve endothelial cell function and promote angiogenesis. For example, GLP-1 RAs can restore EPC function by improving mitochondrial function and autophagic flux; Restoring endothelial cell mitochondrial function is a crucial strategy for improving angiogenesis in DW (Lu et al., 2024). metformin can protect endothelial cells from methylglyoxal (MGO)-induced apo ptosis by inhibiting ROS (Wang G. et al., 2022; Ding et al., 2025) (Figure 3).

5.2. Nanomaterial-based delivery systems and mitochondrial therapy

Nanomaterials offer a powerful platform for precise mitochondrial-targeted therapy. For example, mesoporous polydopamine nanoparticles can be loaded with the mitochondria-protective peptide SS-31 and incorporated into hydrogels, achieving synergistic photothermal antibacterial effects and mitochondrial function maintenance in a diabetic mouse full-thickness wound model, resulting in 40% faster wound closure compared to controls and improved histological outcomes including enhanced re-epithelialization and collagen deposition (Deng et al., 2023) (Table 2). Carbon dot-based nanozymes (e.g., Zn/C-dots) possessing SOD and CAT-like multi-enzyme activities effectively scavenged ROS and exerted antibacterial effects against both S. aureus and E. coli. When encapsulated in ROS-responsive hydrogels, they enabled localized and sustained release tailored to the wound microenvironment, significantly reducing wound area, bacterial load, and inflammatory cytokine levels in diabetic mice (Dai et al., 2024) (Table 2). The CTH@MN system (CeO₂@Tau@Hydrogel@Microneedle), leveraging taurine’s anti-senescence properties and cerium oxide’s mtROS-scavenging ability, successfully inhibited the ROS/NF-κB pathway and activated autophagy in diabetic wounds, attenuating oxidative damage and inflammation while countering cellular senescence to create a pro-regenerative immune microenvironment (Tian et al., 2024; Singh et al., 2023; Koo et al., 2023) (Table 2). Collectively, these nanomaterial-based approaches demonstrate that precise mitochondrial targeting, combined with microenvironment-responsive release and multi-functional activities (antioxidant, antibacterial, anti-senescence), can significantly enhance diabetic wound healing by addressing multiple pathological factors simultaneously.

5.3. Natural products, extracellular vesicles, and mitochondrial quality control

Emerging evidence highlights ROMO1 (Reactive Oxygen Species Modulator 1) as a critical mitochondrial inner membrane protein that governs mtROS generation and macrophage polarization in diabetic wounds. ROMO1 is known to regulate mitochondrial ROS bursts through its association with the electron transport chain, and its dysregulation has been implicated in various oxidative stress-related pathologies (Zhu et al., 2019). In the context of diabetic wound healing, a recent study developed a redox-responsive chitosan hydrogel loaded with mitochondria-targeted fullerenol (C60@QM-HG) that modulates mitochondrial redox status via the HSPA8-ROMO1 signaling axis (Wu et al., 2026). This system achieved controlled release of C60(OH)n through reversible borate ester bonds, enabling tailored antioxidant effects under diabetic wound conditions. Mechanistically, C60@QM-HG targeted mitochondria to regulate the M1/M2 macrophage balance through the HSPA8-ROMO1 pathway, resulting in significant antioxidant and anti-inflammatory effects. By suppressing M1 polarization and promoting the transition to the anti-inflammatory M2 phenotype, this intervention improved the inflammatory microenvironment, accelerated re-epithelialization and collagen deposition, and enhanced healing of diabetic and infected wounds. Furthermore, to enhance mitochondrial targeting, C60(OH)n was conjugated with Apoptozole (an HSPA8 inhibitor), yielding AP&C60@QM-HG, which further suppressed M1 polarization and promoted diabetic wound healing (Wu et al., 2026).

Mitochondrial transfer is emerging as a key therapeutic mechanism, facilitated by both engineered nanomaterials and natural vesicles. For instance, a smart tungstate-chitosan oligosaccharide (WOC) nanoplatform promotes M2 macrophage polarization and subsequent vesicle-dependent mitochondrial transfer to endothelial cells, restoring vascular function and accelerating wound healing (Dai et al., 2024; He et al., 2024; Qin et al., 2025; Huang et al., 2025) (Table 2). In parallel, mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) deliver functional mitochondria to dysfunctional neutrophils in the wound site. This transfer restores neutrophil bioenergetics via mitochondrial fusion, thereby inhibiting the formation of neutrophil extracellular traps (NETs) and breaking the cycle of NET-induced endothelial ferroptosis, which ultimately promotes angiogenesis and repair (Lu et al., 2024). This multifaceted approach, often combined with anti-inflammatory signaling, positions MSC-EVs as a promising cell-free therapy (Ding et al., 2025; Lu et al., 2024) (Table 2). In addition, restoring mitophagy has emerged as a novel strategy for DW treatment. Research indicates that enhancing mitophagy through pharmacological or genetic means can significantly improve DW healing. For example, Glucagon-like peptide-1 (GLP-1) receptor agonists can restore endothelial progenitor cell function by improving mitophagic flux; natural compounds like resveratrol can promote mitophagy via Sirtuin 1 (SIRT1) activation (Ding et al., 2025) (Figure 2D).

Collectively, these mitochondria-targeted therapeutic strategies—ranging from direct antioxidant approaches and metabolic modulation to quality control enhancement and mitochondrial transfer—address distinct but interconnected aspects of mitochondrial dysfunction in diabetic wounds (Table 2). While the majority of these approaches have been validated primarily in preclinical animal models, several have established safety profiles in human trials for other indications: MitoQ has completed Phase II trials for Parkinson’s disease and hepatitis C with favorable safety outcomes (Zhang H. et al., 2025); resveratrol has been extensively studied in human metabolic disease trials (Erol Doğan et al., 2024; Corbi et al., 2023); and mesenchymal stem cell-derived extracellular vesicles are currently in early-phase clinical trials for various inflammatory conditions (Lightner et al., 2023; Chu et al., 2022). These safety data, combined with promising preclinical efficacy in DW models, support the translational potential of mitochondria-targeted interventions for diabetic wound care.

6. Discussion and outlook

Translating intervention strategies targeting the mitochondria-inflammation axis from basic research to clinical applications for DW still faces a series of critical challenges. First, the precision of mechanistic understanding and the complexity of translation represent the primary obstacles. Although the central roles of mtROS, mtDNA leakage, and the NLRP3/cGAS-STING pathways in driving chronic inflammation in DW have been established, the specific regulatory networks of these events across different stages of wound healing and various cell types (such as macrophages, fibroblasts, and keratinocytes) remain unclear. This directly limits the development of therapies capable of precisely interrupting the vicious cycle of inflammation without compromising normal immune surveillance.

In the advancement of treatment strategies, although approaches like mitochondria-targeted antioxidants (e.g., MitoQ) and macrophage metabolic reprogramming (e.g., SDH inhibitors) have shown significant efficacy in animal models, their clinical translation faces severe challenges in targeted delivery and microenvironment adaptation. The unique pathological microenvironment of DW—including persistently high ROS levels, high protease activity, and pH fluctuations—poses significant challenges to drug stability, retention, and bioactivity. Emerging smart nanotechnologies, such as ROS-responsive hydrogels, triggerable nanozymes (e.g., Zn/C-dots), and active mitochondrial delivery systems based on extracellular vesicles, offer breakthrough potential for achieving spatiotemporally precise drug control and release, along with synergistic antioxidant, anti-inflammatory, and antibacterial effects. However, the inherent biosafety, large-scale production processes, and cost-effectiveness of these complex systems are practical issues that must be resolved before they can enter clinical practice.

Furthermore, mitochondrial transfer, as a cutting-edge technology, provides a novel paradigm for addressing the aforementioned challenges. Research indicates that EVs derived from mesenchymal stem cells (MSCs) or M2 macrophages can horizontally transfer intact functional mitochondria to damaged cells (such as endothelial cells and inflammatory neutrophils) at the DW site. This natural “organelle replacement therapy” directly supplies healthy mitochondria to functionally compromised cells, thereby restoring cellular ATP generation capacity at the root, reducing mtROS levels, and decreasing the release of pro-inflammatory factors (e.g., IL-1β, IL-18). More intriguingly, this transfer is not merely a simple “energy transfusion”; it can also reshape the metabolic state of recipient cells, for instance, by promoting a return to OXPHOS, which is crucial for inducing macrophage polarization toward the reparative M2 phenotype. However, the translational application of this technology still requires optimization of its engineering strategies, such as improving mitochondrial loading efficiency, endowing EVs with “homing” capabilities to target specific diseased cells, and ensuring standardized and safe large-scale production.

The need for personalized medicine is particularly prominent in the field of DW. Future research must integrate multi-omics analyses to identify biomarkers that can predict therapeutic responses, thereby determining which patients are more likely to benefit from different strategies such as mitochondrial transfer, antioxidant, or anti-inflammatory therapies. The daunting task of clinical validation cannot be overlooked. Whether for EV-based biologics or complex nanomedicines, advancing their clinical application necessitates rigorously designed clinical trials to verify their safety and efficacy in promoting healing in humans.

Finally, with the global prevalence of diabetes continuing to rise, developing innovative therapies that can reverse chronic inflammation in DW and fundamentally promote healing holds significant social and economic importance. Cutting-edge technologies represented by extracellular vesicle-mediated mitochondrial transfer signify a shift in diabetic wound treatment from traditional “pharmacological intervention” to an innovative “organelle repair” era. Future research should focus on bridging the entire chain from “mechanistic understanding” to “technological innovation” and finally to “clinical validation,” employing multidisciplinary and synergistic strategies to ultimately bring truly effective mitochondria-targeted therapeutic options to DW patients.

Funding Statement

The author(s) declared that financial support was not received for this work and/or its publication.

Author contributions

YC: Writing – original draft, Funding acquisition, Formal Analysis, Resources, Software, Supervision, Conceptualization, Writing – review and editing, Investigation, Data curation, Validation. HL: Visualization, Validation, Methodology, Resources, Conceptualization, Investigation, Writing – review and editing, Writing – original draft, Project administration, Supervision, Software. WH: Data curation, Investigation, Methodology, Supervision, Writing – review and editing, Software, Conceptualization, Resources, Writing – original draft, Formal Analysis, Project administration, Visualization, Validation.

Conflict of interest

The author(s) declared that this work was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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The author(s) declared that generative AI was not used in the creation of this manuscript.

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Glossary

AGEs

Advanced Glycation End products

AMPK

AMP-activated protein kinase

Arg1

Arginase 1

ASC

Apoptosis-associated speck-like protein containing a CARD

ATP

Adenosine Triphosphate

BA

Baicalin

BH4

Tetrahydrobiopterin

CAT

Catalase

C-dots

Carbon dots

cGAS

cyclic GMP-AMP Synthase

Cyt c

Cytochrome c

DAMPs

Damage-Associated Molecular Patterns

DW

Diabetic wounds

DMM

Dimethyl Malonate

Drp1

Dynamin-related protein 1

ECM

Extracellular Matrix

EGF

Epidermal Growth Factor

EPCs

Endothelial Progenitor Cells

ETC

Electron Transport Chain EVs Extracellular Vesicles

Fenton reaction

Fenton reaction

GPx

Glutathione Peroxidase

GTP

Guanosine Triphosphate

HG

HyperGlycemia

HIF-1α

Hypoxia-Inducible Factor 1-alpha

IFN

Interferon

IκBα

Inhibitor of Kappa B Alpha

IL

Interleukin

iNOS

inducible Nitric Oxide Synthase

IRF3

Interferon Regulatory Factor 3

MAPK

Mitogen-Activated Protein Kinase

MDA

Malondialdehyde

Mfn1/2

Mitofusin 1/2

MMPs

Matrix Metalloproteinases

MOFs

Metal-Organic Frameworks

MPs

Mitochondria-targeted Peptides

mPTP

mitochondrial Permeability Transition Pore

MSCs

Mesenchymal Stem Cells

mtDNA

mitochondrial DNA

mtROS

mitochondrial Reactive Oxygen Species

NF-κB

Nuclear Factor Kappa B

NLRP3

NLR Family Pyrin Domain Containing 3

NO

Nitric Oxide

Nrf2

Nuclear factor erythroid 2-related factor 2

OPA1

Optic Atrophy 1

OXPHOS

OXidative PHOSphorylation

PDGF

Platelet-Derived Growth Factor

PHD

Prolyl Hydroxylase

PINK1

PTEN-induced Kinase 1

RAGE

Receptor for AGEs

ROS

Reactive Oxygen Species

SDH

Succinate Dehydrogenase

SIRT1

Sirtuin 1

SOD

Superoxide Dismutase

STING

Stimulator of Interferon Genes

TCA

Tricarboxylic Acid

TGF-β

Transforming Growth Factor-Beta

TIMPs

Tissue Inhibitors of Metalloproteinases

TNF-α

Tumor Necrosis Factor-Alpha

TPP+

Triphenylphosphonium

VEGF

Vascular Endothelial Growth Factor

ΔΨm

Mitochondrial Membrane Potential