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Frontiers in Biomaterials Science ·

Volume 5 - 2026 | https://doi.org/10.3389/fbiom.2026.1979352

Immunotechnology-based toolbox for care of chronic wounds

  • Munishwar Nath Gupta1
  • Premlata Ambre2*corresponding author
  1. 1Department of Biochemical Engineering and Biotechnology, Indian Institute of Technology Delhi, New Delhi, India
  2. 2Department of Pharmaceutical Chemistry, Bombay College of Pharmacy, Mumbai, India
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Abstract

Wound healing is a complex natural process with overlapping sequences of inflammatory, proliferation, and remodeling stages. All stages involve immune cells and their secreted molecules, including macrophages, neutrophils, and cytokines. This process becomes dysregulated in chronic wounds, such as diabetic ulcers and malignant (fungating) wounds, where healing halts before it can be completed. Both generic immunomodulation and targeted immunoengineering approaches constitute a powerful toolbox to reset healing processes. This brief review first provides background on the involvement of immune system components contribute to wound healing and their dysregulation during impaired wound healing. It then discusses the current state of knowledge on immunomodulation and immunoengineering as applied to chronic wound care. The immunomodulation approach uses stem cells or extracellular vesicles to regulate inflammation and prevent cellular senescence so that tissue regeneration takes place. Immunoengineering approaches cover the use of DNA nanoparticles to aid tissue regeneration, and aptamer-antibody conjugates to control inflammation. Finally, theranostic devices which provide real-time sensing and delivery of necessary proteins and drugs to reset wound healing have been discussed.

Keywords

1 Introduction

Wound healing is a dynamic process it typically involves four overlapping stages: haemostasis, inflammation, tissue proliferation, and remodeling (Falanga et al., 2022). Acute wounds commonly result from surgery, trauma, burns, cuts, abrasions, punctures, lacerations, skin tears, and donor-site procedures, and they generally heal within a predictable timeframe. In contrast, chronic wounds fail to progress through the normal stages of healing and may persist because of sustained inflammation, infection, impaired vascularization, hypoxia, or underlying disease. Common examples include diabetic foot ulcers [DFU], venous and arterial ulcers, pressure injuries, neuropathic ulcers, non-healing surgical wounds, radiation ulcers, malignant/fungating wounds, vasculitis ulcers, pyoderma gangrenosum, and chronic traumatic ulcers (Pedaprolu et al., 2025; Mishra et al., 2024) Although several pathological features are shared across these conditions, some dysregulated processes are disease-specific; for example, diabetic wounds or malignant wounds exhibit distinct physiological/pathological changes (Sun et al., 2016).

The growing burden of diabetes, ageing, vascular disorders, and surgical interventions has made effective wound management an important global healthcare priority. It is estimated that 1%–2% of the global population experience chronic wounds, with diabetic wounds contributing to a limb amputation approximately every 30 s worldwide. The substantial clinical and economic burden of chronic wounds has resulted in the development of advanced dressings designed to actively and, ideally, in real time, modulate the healing process (Mishra et al., 2024; Murray et al., 2018; Gupta et al., 2025).

The cells and molecules of the immune system play important roles in both natural healing processes and their dysregulation. Hence, the immunotechnology-based toolbox serves as an important part of the chronic wound care. This brief review discusses this toolbox after providing the necessary background and context.

2 Which processes get dysregulated in general?

One crucial factor behind wounds becoming nonhealing is that the duration of the inflammation phase becomes longer (Avishai et al., 2017). Inflammation is a part of the defense mechanism of the body in response to invasion by physical, chemical or microbial agents. The ancients recognised it by rubor, tumour, calor, and dolour. These respectively referred to redness [due to the increased blood flow to the affected site]; swelling [due to accumulation of fluid at the site]; heat as the affected part felt warmer and pain felt at the part invaded by any of the above kinds of agents. An acute inflammation [for example, as part of the normal healing in an acute wound] can last for minutes or may persist for few days at the most. It results from the response of the immune system primarily via PMNs [polymorphonuclear neutrophils], the leucocytes which are part of the innate immunity and act as the first responders in such cases. In chronic wounds, apart from infection, persistent inflammation is also caused by other mechanisms. The presence of damage-associated molecular patterns [DAMPs] on necrotic tissue, microvascular impairment, ischemia-reperfusion injury, and metabolic issues notably hyperglycemia [in diabetic wounds] and oxidative stress also lead to continuation of inflammation. Cellular senescence and neuropathy also contribute to this in specific situations (Huang et al., 2024; Zhao et al., 2016). The result of these factors also keeps innate immunity related cells, notably neutrophils and macrophages locked in pro-inflammatory forms (Pastar et al., 2023). While it is true that underlying chronicity is a complex cross-talk between microbial burden and intrinsic host factors like ischemia, diabetes and tissue hypoxia, etc.; about 60%–80% chronic wounds harbor biofilms (Schilrreff and Alexiev, 2022; Versey et al., 2021).

The swelling part of inflammation is due to vascular changes. Injured tissue, macrophages, and mast cells [in the case of infection, right at the beginning] release mediators that cause vasodilation. This facilitates not only the increase in blood flow, which brings in helpful cells; the changes in the endothelial part of the vessels induce secretion of adhesion factors, which also help with transport of leucocytes to the injured site. During inflammation, the wound area, including the extracellular matrix, is invaded by platelets, macrophages and finally by stem cells, all together releasing growth factors which promote fibroblast activation (Robson, 1997; Irfan-maqsood, 2018). This sets the stage for transition to the proliferative phase if the healing follows normal path, as happens in the case of acute wounds. A complex step terminates the inflammation phase and, almost simultaneously, activates the repair mechanisms that operate in the proliferative phase.

This termination step consists of inhibitors of pro-inflammatory cytokines [IL-1, TNF α, IL-6, IL-12], including their soluble receptors, coming into play. Also, the inhibitors of components of the hemostasis and thrombosis system, along with the release of anti-inflammatory cytokines [IL-4, IL-10, TGF β], together shut down inflammation.

In chronic wounds, the inflammatory step is prolonged and needs therapeutic interventions to dampen it so that the healing is resumed. A key event is that the transition of M1 macrophage [which secretes TNF-α, IL-1 β, IL-6 etc.,] to M2 type macrophage does not take place. M2-type macrophages secrete reparative biologicals like IL-10, TGF-β, and arginase 1 (Cao et al., 2024).

Figure 1 illustrates the dynamic transition from persistent M1-like inflammation to an M2-like reparative phenotype during chronic wound healing. The M1-like phenotype maintains persistent inflammatory danger signals, such as DAMPs or PAMPs [pathogen-associated molecular patterns], and NF-κB-associated signals. This results in elevated ROS and pro-inflammatory cytokine levels. In a resolving wound microenvironment, signals such as IL-10, TGF-β, and metabolic reprogramming promote a transition toward an M2 thereby supporting growth-factor production, ECM synthesis, tissue remodeling, and wound repair.

Simplified representation of macrophage phenotypic transition during chronic wound healing.
Figure 1. Simplified representation of macrophage phenotypic transition during chronic wound healing.

Although macrophage activation has historically been categorized under a binary M1 [classically activated] versus M2 [alternatively activated] paradigm, the diverse and changing microenvironments of chronic wounds act as stimuli to lead to formation of multiple phenotypes of macrophages with overlapping functionalities (Murray et al., 2014). Single-cell transcriptomic and functional profiling studies have shown that transitions of these phenotypes are dynamic in nature (Celik et al., 2024; Kim and Nair, 2019). Notably, M2a, M2b, M2c and M2d display different cell surface markers. M2a is induced by IL-4 and IL-3 and help in regulation of healing and repair phase (Anderson et al., 2008). Higher expression of CD 206 [a mannose receptor] enables this subtype to destroy apoptotic cells, clear debris and initiate healing. M2b formed in response to the presence of immune complexes and TLR agonists such as lipopolysaccharides. This subtype secretes anti-inflammatory IL-10. M2c carries scavenger receptor CD163 which helps in clearing haptoglobin and hemoglobin complexes. M2d is observed during tissue repair in response to signaling in the form of IL-4R alpha.

The higher level of expression of markers like CD86 and inducible nitric oxide synthase [iNOS] indicate a predominantly pro-inflammatory and cytotoxic state. On the other hand, higher expression of CD206 [mannose receptor C-type 1] and arginase-1 [Arg1] reflects a reparative state that enable collagen synthesis, and extracellular matrix reconstruction (Szondi et al., 2021). The sub-populations often coexist; these markers signify dynamic functional programs; in fact, intermediate states co-expressing both pro-inflammatory and reparative markers have been identified (Kim and Nair, 2019).

During infection, pathogens release molecules which favour formation of M2 phenotypes whereas host cells prefer M1 so that pathogen is destroyed. The type of pathogen [in fact to the level of a particular strain] and state of the disease dictate the nature of subtypes of macrophages. This explains why pro-inflammatory and reparative macrophage phenotypes can co-exist (Strizova et al., 2023).

An illustrative example is what happens in the case of DFU. Hyperglycemia blocks M1—> M2 switch. The pro-inflammatory cytokines sustain the inflammation. Particularly, TNF-αand IL-1β suppress the migration and proliferation of keratinocytes and fibroblasts which prevents the wound closure. The formation of advanced glycation end products triggers cascades like NF-kB which also prolong inflammation (Wu et al., 2022).

As the M1 to M2 transition involves macrophage conversion from one extreme functional state [pro-inflammatory] to another extreme opposite functional state, it is often called polarization [with the analogy of north and south poles of a magnet] (Davis et al., 2013). While this is adequate to understand the role of macrophages in inflammation and wound healing, in reality the roles of these two types of macrophages in various pathogenic conditions are more nuanced (Strizova et al., 2023; Guan et al., 2025).

The transition from inflammatory role to the reconstruction phases also requires that matrix metalloproteinases [MMPs] are regulated/controlled by their tissue inhibitors [TIMPs]. Their role in clearing up damaged tissue is over. In chronic wounds, this does not happen. This results in their continuing to hydrolyse ECM components and thus preventing reconstruction of the new tissue at the wound site. Oxidative stress also causes continued proteolysis and apoptosis (Goldman, 2004).

3 Immunomodulation and immunoengineering in care of chronic wounds

From above discussion it should be obvious that immune system plays a critical role in wound healing. And chronic wounds occur when these healing processes are hampered. An important element is that a non-healing wound, devoid of the skin as a barrier, is highly prone to infection. Biofilm formation by pathogenic bacteria further complicates infection control. The immune system is again responsible for fighting these infections. Hence it is not surprising that immunomodulation is a powerful approach for treatment of chronic wounds.

The immunology based toolbox consists of following broad classes of strategies which are discussed in this review. These strategies are aimed at transforming the wound microenvironments to the healing and reparative phase.

  • Immunomodulation consists of the regulation of the transition of immune-cell phenotypes and their effector functions such that inflammatory processes are replaced by the healing and reparative phase. This is enabled by agents which favour immune responses accordingly (Mantovani et al., 2013).
  • Immunoengineering, on the other hand, exploits engineered biomaterials including nanoparticles, cell-based therapies, and novel designs of delivery of therapeutics that regulate immune responses in a spatio-temporal manner (Hubbell et al., 2009; Irvine et al., 2015).
  • Regenerative immunoengineering ensures that immunological activity aligns well with tissue reconstruction. Towards that, these strategies focus on ending chronic inflammation and include transformation of pro-inflammatory macrophage phenotypes to M2 subtypes; ECM remodeling and tissue regeneration (Badylak et al., 2008; Hutmacher et al., 2015; Sadtler et al., 2016).

The technologies discussed below are not passive delivery platforms; their physicochemical identity is itself an immunomodulatory signal. Surface chemistry governs protein adsorption and macrophage adhesion, with hydrophilic, anionic surfaces favouring reparative M2 polarization over pro-inflammatory M1 activation, while substrate stiffness acts through mechanotransduction, softer, tissue-matched materials promoting M2 skewing and cell migration and stiffer matrices favouring fibrosis (Hang et al., 2026). Porosity and pore architecture govern immune-cell infiltration, vascularization and nutrient exchange, while degradation rate and degradation by-products set the duration and intensity of the foreign-body response. Swelling behaviour affects diffusion of oxygen, nutrients and cytokines within the material but can also compress local capillaries, and oxygen permeability itself drives HIF-1α-mediated angiogenesis and the hypoxia-to-normoxia switch that accompanies the M1-to-M2 transition (Engler et al., 2006). Release kinetics determine whether an immunomodulatory or growth-factor cargo achieves a sustained therapeutic window or an ineffective early burst, and electrical and mechanical cues, acting through endogenous wound electric fields and mechanosensitive pathways such as the NLRP3 inflammasome, further shape macrophage polarization and cell migration (Cui et al., 2025). Because these properties act synergistically rather than independently, the sections below return repeatedly to how a platform’s composition, not only its cargo, shapes the immune microenvironment it creates.

3.1 Extracellular vesicles and how these can be used for immunomodulation?

Extracellular vesicles (EV) are small sacs enclosed by lipid bilayers which are released by all cell types as a part of inter-cell communication (Doyle and Wang, 2019). These are essentially cell-free vectors which can transfer the cargo of proteins or lipids or nucleic acids or metabolites between nearby or even distant cells. Their compositions depend upon the parent cells and even cytosolic components are parts of EVs.

In vitro, EVs can be used to transfer therapeutic agents to the site of chronic wounds. Exosomes are perhaps most extensively studied and have a size range of 30–150 nm. Microvesicles have sizes in the range of 100–1,000 nm. The third kind, apoptotic bodies are in size range of [50–5000 nm]. The techniques for their isolation and characterization have been described in the literature (Gardiner et al., 2016). Exomers, non-membranous nanovesicles [size <50 nm], have also been reported but not yet investigated extensively (Al-Jipouri et al., 2023).

It may be useful here to compare EVs with liposomes, which have a long history of utility as drug delivery vehicles (Van Der Koog et al., 2022; Ma et al., 2026). EVs are naturally occurring entities and the composition of the lipids in their bilayers is far more complex and diverse as compared to liposomes which are synthetic products. That enables their engineering to suit a specific system, these can be easily produced at large scale and as a homogeneous population. EVs suffer from the usual constraints associated with any natural product in terms of scalability, downstream processing costs and heterogeneity. The hybrids of liposomes and EVs have also been explored as drug delivery vehicles (Van Der Koog et al., 2022). Uni-lamellar, multi-lamellar, and multi-vesicular [where many vesicles are enclosed in the same membrane] liposomes have been described. The liposomes can carry positive, negative or nearly zero surface charge, EVs have negative surface charge. Unlike liposomes, EVs have a variety of membrane proteins inherited from the parent cells. This difference in surface chemistry is not incidental to function; the anionic, glycoprotein- and phosphatidylserine-rich EV surface favours recognition by macrophage scavenger receptors and an efferocytosis-like, anti-inflammatory uptake route, whereas the more tunable and often cationic liposomal surface can trigger stronger complement activation and pro-inflammatory uptake unless engineered [e.g., PEGylated] to avoid it. Surface charge and chemistry are therefore as much a determinant of the vesicle’s immunomodulatory outcome at the wound site as the cargo it carries (Anderson et al., 2008). In fact, engineered EVs have a huge utility in delivery of therapeutic proteins. Inserting proteins in liposomes has been tried but EVs score over liposomes for such applications by delivering proteins present in their membrane or lumen. Another major advantage of EVs is that [unlike liposomes] they carry carbohydrates [which can be exploited for targeted delivery] and proteoglycans similar to the ECM. EVs can home to cells similar to their parent cells and have been explored for “Trojan horse targeting therapy”. EVs also have better stability and safety profile. These don’t produce inflammation or cell death. In fact, apoptotic EVs clear dead/damaged tissue/cell debris and promote tissue repair. Nevertheless, liposomes, as a more proven technology, continue to attract attention in wound care (Ma et al., 2026).

3.2 Stem cells help in the healing of chronic wounds

Stem cell therapies generally encompass four main pillars: identifying suitable cell sources, selecting appropriate delivery methods, activating critical therapeutic mechanisms of action, and ultimately achieving positive clinical outcomes. As illustrated in Figure 2, stem cell-based interventions target key bottlenecks in non-healing wounds through paracrine signaling, phenotypic switching of inflammatory cells, and neovascularization. However, while preclinical models frequently demonstrate near-complete dermal restoration, translation to clinical efficacy remains variable and largely investigational (Huynh et al., 2022; Farabi et al., 2024; Velikic et al., 2025). Clinical trials frequently encounter challenges such as limited cell persistence within the proteolytic wound bed, donor heterogeneity, and incomplete tissue remodeling rather than true scarless regeneration. Therefore, these outcomes highlight therapeutic potential under evaluation rather than universally established clinical endpoints.

Overview of investigational stem cell platforms in chronic wound management: Sources, delivery modalities, molecular mechanisms, and prospective tissue outcomes. (1) Stem cell and progenitor sources, including adult mesenchymal stem/stromal cells [MSCs derived from adipose, bone marrow, and umbilical cord/placental tissues], induced pluripotent stem cells [iPSCs], and lineage-reprogrammed somatic cells. (2) Common experimental and clinical delivery strategies [topical hydrogel/spray application, bio-scaffold incorporation, localized intradermal/subcutaneous injection, and systemic vascular infusion]. (3) Primary proposed paracrine mechanisms: pro-resolving immunomodulation [M1 \to M2 macrophage polarization], neo-angiogenesis, re-epithelialization/cell migration, extracellular matrix [ECM] remodeling, and direct/indirect antimicrobial activity. (4) Prospective wound-bed outcomes: Transition from a non-healing chronic inflammatory state toward tissue closure. *Note:* Fully restored, scarless dermal architecture represents an idealized therapeutic target; while early-phase trials and preclinical models demonstrate accelerated epithelialization and reduced wound area, definitive clinical efficacy across heterogeneous etiologies remains under active investigation.
Figure 2. Overview of investigational stem cell platforms in chronic wound management: Sources, delivery modalities, molecular mechanisms, and prospective tissue outcomes. (1) Stem cell and progenitor sources, including adult mesenchymal stem/stromal cells [MSCs derived from adipose, bone marrow, and umbilical cord/placental tissues], induced pluripotent stem cells [iPSCs], and lineage-reprogrammed somatic cells. (2) Common experimental and clinical delivery strategies [topical hydrogel/spray application, bio-scaffold incorporation, localized intradermal/subcutaneous injection, and systemic vascular infusion]. (3) Primary proposed paracrine mechanisms: pro-resolving immunomodulation [M1 \to M2 macrophage polarization], neo-angiogenesis, re-epithelialization/cell migration, extracellular matrix [ECM] remodeling, and direct/indirect antimicrobial activity. (4) Prospective wound-bed outcomes: Transition from a non-healing chronic inflammatory state toward tissue closure. Note: Fully restored, scarless dermal architecture represents an idealized therapeutic target; while early-phase trials and preclinical models demonstrate accelerated epithelialization and reduced wound area, definitive clinical efficacy across heterogeneous etiologies remains under active investigation.

After 3–5 days of fertilization of egg, a cluster of cells called blastocyst is formed. The inner part of this cell mass constitutes pluripotent embryonic stem cells. These can differentiate into any cell type [tissue/organ]. On the other hand, multipotent cells have a more restricted ability to differentiate. Bone marrow contains hematopoietic cells which differentiate to form all types of blood cells. Adipose-derived stromal cells are an important and extensively investigated type of mesenchymal stromal cell and can differentiate into bone, cartilage, muscle, tendons, blood vessels, lymphatic network and fat cells. MSCs are adult stem/progenitor cells and harvested from bone marrow, adipose tissues, dental pulp. MSCs also occur in placenta, amniotic fluid and embryonic tissues (Zakrzewski et al., 2019).

The stem cells of brain, skin, muscle, liver and teeth can help maintain or repair the corresponding tissue/organ but can not heal in case of extensive damage. Foetal stem cells at various stages of gestation can be obtained from liver, blood, bone marrow, amniotic fluid and placenta. Foetal stem cells are much more multipotent as compared to those multipotent stem cells which are derived from adult cells mentioned above. It is now possible to induce adult stem cells to become pluripotent cells [iPPCs] (Della Rocca et al., 2025).

The stem cells used for clinical applications are MSCs, endothelial progenitor cells [EPCs] and iPPCs. The immunomodulatory effects of MSCs in chronic wounds operate via paracrine mechanisms. These mechanisms promote survival, migration and proliferation of cells at the wound site (Lorenz et al., 2016). As bone marrow MSCs are a scarce resource, those from adipose tissues have been used more often for clinical purpose in recent times. A useful observation is that, rather than isolated stem cells, cruder fractions [such as stromal vascular fraction obtained from adipose tissue or bone marrow mononuclear cells] work better at promoting angiogenesis and osteogenesis. Thus, synergy of multiple cells is helpful. As even the secretome from culture medium growing MSCs from adipose tissue facilitates cell migration at wound sites, the paracrine mechanisms definitely seem to play a large role. EPCs have been shown to promote angiogenesis by transformation of the circulating progenitor cells. Embryonic stem cells are allogeneic when used in adults, but iPPCs from adults can overcome this constraint. However, the possibility of these leading to malignancy has been a great concern (Lorenz et al., 2016).

The bone marrow stem cells suppress cytotoxic T cells and B cells at wound site to reverse pro-inflammatory conditions in chronic wounds. The MSCs also control infection by secreting antimicrobial peptides such as LL-37. MSCs also have been found to tolerate hypoxia much better. However, the inhibition of migration and proliferation of stem cells of adipose tissue and much reduced effect of the secreted peptide than expected are reality checks for stem cell therapy (Lorenz et al., 2016).

Raghuram et al. (2020) few years back have provided a comprehensive survey of the applications of various kinds of stem cells in treatment of chronic wounds (Raghuram et al., 2020). As not entirely expected, it shows mixed results due to inherent challenges of the approach. An updated picture on results with MSCs from various sources is now available in the review by Tang et al. [2026] (Tang et al., 2026). What is impressive is that MSCs are useful at all the stages of wound healing. MSCs establish hemostasis and wound closure. Their anti-inflammatory cytokines like IL-10 and TGF-beta control inflammation. These downregulate NF-κB/NLR family pyrin domain containing protein 3 [protein of the immune system] and favour M2 macrophage formation.

While potentially MSCs can differentiate into fibroblasts, endothelial cells and keratinocytes, the direct participation of this process in reality remains debatable. The role of MSCs senescence under chronic wound conditions and how much it impairs their beneficial effects continues to remain an active area of research (Tang et al., 2026). Finally, EVs of MSCs are proving to be highly useful in wound healing, especially via paracrine signaling.

Farabi et al. (2024) have also discussed the various ways stem cell therapy has been used in wound healing (Farabi et al., 2024). Patches of novel biomaterials and autologous grafts have also shown promise. The biomaterial scaffold itself influences healing process. The softer, skin-like scaffolds support regenerative MSC and M2 macrophage responses, while stiffer scaffolds may promote fibrosis. Scaffold porosity and pore connectivity also affect oxygen and nutrient supply, influencing inflammatory responses (Hang et al., 2026) The review also mentions the usefulness of small-molecular-weight chemicals/natural products that enhance stem cell efficacy, mostly by facilitating cell migration.

3.3 Immunoengineering approaches

Apart from immunomodulation approaches discussed above, immunoengineering is also developing into a powerful tool for chronic wound care. Muire et al. (2022) mention using DNA encoded for VEGF in nanospheres and aptamers targeting toll-like receptors to strengthen acquired immune responses, or cytokines to dampen cytokine storm (Muire et al., 2022). The authors also discuss the potential of theranostic approaches. A smart dressing which uses a near-infrared [NIR] sensor to detect hypothermia as a result of infection and an integrated UV-actuated LED triggers the release of an antibiotic (Muire et al., 2022). This is an example of stimulus-triggered release kinetics engineered directly into the material, rather than achieved through drug formulation alone.

Antimicrobial proteases delivered via hydrogel dressings inhibit biofilm formation and damage existing biofilms. The mesh size and swelling ratio of the hydrogel not only govern the enzyme payload, but also provide sufficient porosity; a highly swollen network allows the protease to diffuse into and disrupt the biofilm’s extracellular polymeric matrix, while that same swelling controls exudate absorption and maintains a moist, yet sufficiently oxygen-permeable, environment (Hang et al., 2026). Lysostaphylococcus [lysostaphin] protease is a zinc metalloenzyme and even local application of these ions is known to encourage cell proliferation and production of VEGF and insulin-like growth factors. The dressings with antibacterial proteases have been demonstrated to be effective in care of burn wounds (Chen et al., 2023).

Bao et al. (2024) have described a hydrogel based upon porcine dermal matrix loaded with curcumin and glass nanoparticles doped with Mg ions (Bao et al., 2024). After released curcumin has controlled infection, the metal ions dampened several pro-inflammatory pathways. This sequential effect depends on the degradation pathway of the material. Glass dissolution controls Mg2+ release, while hydrogel degradation and swelling control curcumin release. Both release profiles must be coordinated so the antimicrobial phase transitions smoothly into the anti-inflammatory phase. Such approaches indicate that the dividing line between immunomodulation and immunoengineering approaches is rather thin. Recently, a smart nanofibrous patch has been described which inhibits inflammatory factors and promotes angiogenesis (Ghosh et al., 2025). It has been rightly pointed out that immunomodulation by the frequently investigated approach of delivery of growth factors can often give disappointing results unless a reset of M1 to M2 macrophages is carried out by what has been referred to as “regenerative immunoengineering” (Wu et al., 2022). Working with a fibroblast growth factor, these authors report that the growth factor worked much better in production of collagen and ECM after a smart material was used to ensure above stated reset of the macrophages (Wu et al., 2022).

3.4 Infection and the wound microbiome

Persistent infection in chronic wounds is due to the pathogens being present inside an extrapolysaccharide matrix forming a biofilm that resists both immune functions and antimicrobial treatments. (Zhao et al., 2013). The microbial-associated molecular patterns [MAMPs] such as lipopolysaccharides [LPS], peptidoglycans, and flagellin associated with biofilms are recognised by pattern recognition receptors [PRRs] such as toll-like receptors [e.g., TLR2, TLR4] on invading immune cells (Zhao et al., 2013; Li et al., 2024).

This PRR and cytokine receptor signaling in wounds with the presence of biofilms keep macrophages in M1 state (Krzyszczyk et al., 2018; Yang et al., 2024). These macrophage phenotypes continue to secrete inflammatory cytokines [such as TNF-α and IL-1β], reactive oxygen species [ROS], and matrix metalloproteinases, which degrade nascent extracellular matrix and growth factors and stall the transition to the healing and repair phases (Zhao et al., 2013; Krzyszczyk et al., 2018).

Immunomodulation approaches can help by disrupting the biofilms (Yang et al., 2024; Wang et al., 2025). Hydrolytic enzymes like glycoside hydrolase can destroy extracellular polysaccharide encasing the pathogens. The quorum-sensing inhibitors delivered by hydrogels can also disrupt the biofilms. This leads to liberated bacterial pathogens becoming more amenable to phagocytosis as well as to antibiotics (Zhao et al., 2013).

Engineered biomaterials like cationic polymeric brushes have been used to bind to lipid A of LPS endotoxins to electrostatically sequester circulating anionic endotoxins. Also, nanozymes [e.g., CeO2, MnO2] have been tried for lowering the oxidative stress (Wang et al., 2025). Reprogramming macrophages to M2 type phenotypes by delivery of cytokines such as IL-4 and IL-10 via smart carriers has also been attempted (Krzyszczyk et al., 2018; Yang et al., 2024).

In summary, the above discussed immunomodulatory and immunoengineering tools are further compared in Table 1 across their applications, mechanisms of action, biomaterial/platform composition, wound type, experimental model, major reported outcomes, key limitations, and current translational status, with representative preclinical or clinical studies cited for each.

TABLE 1. Comparative overview of emerging immunotechnology-based platforms for chronic wound care.

TechnologyMechanismBiomaterial/PlatformWound typeExperimental modelMajor outcomeLimitationsTranslational status
Extracellular vesicles (Zhu et al., 2025) (exosomes, microvesicles, apoptotic bodies)Paracrine transfer of proteins/lipids/nucleic acids; low immunogenicityCell-free vesicles (exosomes, microvesicles, apoptotic bodies), 30 nm–5 μmChronic/diabetic woundsDiabetic rodent excisional wounds (STZ/db/db); EVs applied topically/locally; wound closure, re-epithelialization, angiogenesisCell-free targeted delivery (“Trojan horse” homing)Isolation scalability, batch heterogeneity, costPreclinical
Mesenchymal stem cells and crude fractions (Willer et al., 2022) (SVF, BM-MNCs)M1→M2 macrophage shift (IL-10, TGF-β); LL-37 secretion; immune suppressionAutologous/allogeneic MSCs or SVF/BM-MNCDFUPreclinical: diabetic rodent wounds ± BM-MSC/ADSC/SVF. Clinical: RCTs in DFU patients (BM-MNC vs. BM-MSC; SVF)Improved angiogenesis; M2 polarization; mixed resultsSenescence in situ; scarce BM-MSCs; reduced ADSC efficacyEarly clinical, inconsistent
Endothelial progenitor cells (Bao et al., 2024) (EPCs)Angiogenesis via progenitor cell homingAutologous circulating progenitor cellsDFUDiabetic mouse wounds; EPCs injected or mobilized (AMD3100+G-CSF); closure and vascular densityAngiogenesis promotionMinimal mechanistic detail vs. MSCsInvestigational
DNA nanoparticles (Shi et al., 2018) (VEGF-encoding)VEGF gene delivery → angiogenesispoly (lactic-co-glycolic acid) PLGA nanosphere-plasmid DNADFUDiabetic rat foot wounds; VEGF-A (±PDGF-B) nanospheres applied; expression, ulcer closureAngiogenesis promotionDelivery/transfection consistencyPreclinical
Aptamer–antibody conjugates (Zhao et al., 2025)TLR targeting; cytokine dampeningAptamer/antibody conjugatesExtremity woundsGeneric template: excisional/burn mouse wounds, TLR modulation, cytokine profilingImmune/inflammation modulation (qualitative)Specificity/stability in wound bedInvestigational
Theranostic dressing (Qiao et al., 2020) (NIR sensor + UV-actuated antibiotic release)NIR infection sensing; UV-triggered antibiotic releaseSensor–actuator smart dressingInfected extremity woundsInfected mouse/rat wounds (S. aureus/P. aeruginosa); sensor monitoring + triggered release; bacterial load, closureReal-time detection + triggered treatmentDevice complexity, cost, regulatory pathDevice prototype
Antimicrobial protease (Lin et al., 2017) (lysostaphin) hydrogelZn-metalloenzyme disrupts biofilm; Zn2+ aids proliferation/VEGF/IGFHydrogel + antimicrobial proteaseBurn wounds (immunosuppressed)Longitudinal clinical study, immunosuppressed burn patientsEffective biofilm controlNarrow spectrum; immunogenicity; resistanceEarly clinical
Curcumin + Mg-doped glass-nanoparticle hydrogel (Bao et al., 2024)Curcumin antimicrobial; Mg2+ anti-inflammatoryporcine acellular dermal matrix-derived biomaterial (PADM) hydrogel + Mg-bioglass + curcuminInfected chronic woundsMRSA-infected mouse wounds; PADM@MgC applied; bacterial clearance, closure, macrophage polarizationAnti-infection + immune reprogrammingXenogeneic scaffold; MRSA-specific; scale-upPreclinical
Smart stimuli-responsive nanofibrous patch (Zhang et al., 2021)Anti-inflammatory + angiogenesis + monitoringStimuli-responsive nanofiber patchGeneral wound careDiabetic/infected mouse wounds; stimuli-responsive sensors embedded; closure, cytokines, angiogenesisHealing + monitoring (reported)Manufacturing complexity; no validated modelDevice prototype
Regenerative immunoengineering (Dong et al., 2026) (FGF + macrophage-reset smart material)M1→M2 reset + FGF → superior ECM outputSmart biomaterial + FGFDiabetic woundsDiabetic mouse wounds; scaffold + FGF vs. FGF-alone; collagen/ECM, M1/M2 markersSuperior collagen/ECM vs. FGF aloneMechanistic complexity; scale-up unaddressedPreclinical

4 Conclusion and future perspective

The healing of chronic wounds lies at the interfaces of immunology, regenerative medicine, theranostics and smart biomaterials, where surface, mechanical and degradation-related design parameters are as crucial to therapeutic outcomes as the biomolecules these materials carry. Wearables with integrated electronics, telemedicine, along with AI, are obviously parts of the future that are already knocking at the door of the present. As this review has tried to show, the toolbox of immunotechnology will continue to be at the core of these future developments.

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Footnotes

Edited by: Andreea Mariana Negrescu, University of Bucharest, Romania

Reviewed by: Yang Zhu, National University of Singapore, Singapore

Prakhar Varshney, Teerthanker Mahaveer University, India

Statements

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.

Funding

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

Author contributions

MG: Conceptualization, Data curation, Formal Analysis, Investigation, Methodology, Resources, Software, Supervision, Validation, Visualization, Writing – original draft, Writing – review and editing. PA: Conceptualization, Data curation, Formal Analysis, Investigation, Methodology, Resources, Software, Supervision, Validation, Visualization, Writing – original draft, Writing – review and editing.

Acknowledgements

The authors sincerely acknowledge the contributions of Omkar Gadade and Shahid Khan for their assistance in drawing the figures for this manuscript.

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Citation

Gupta, M. N. & Ambre, P. (2026). Immunotechnology-based toolbox for care of chronic wounds. Frontiers in Biomaterials Science, Volume 5. https://doi.org/
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5 - 2026

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Copyright © 2026 Gupta and Ambre.

License: https://creativecommons.org/licenses/by/4.0/

*Correspondence: Premlata Ambre

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