Nanoformulations Loaded with Phytochemicals for Combating Wound Infections and Promoting Wound Healing: Current Applications and Innovations

Abstract

Wounds are broadly classified into acute and chronic types, with chronic wounds being those that cannot heal within 4 to 12 weeks despite treatment. There is a growing interest in efficient and cost-effective wound healing though the drug delivery of active molecules. Natural compounds such as phytochemicals, as well as synthetic molecules with antimicrobial or anti-inflammatory growth factors, can impact tissue regeneration and prevent wound infections. Nanotechnology-based systems, such as polymeric and inorganic nanoparticles and electrospun nanofibrous matrices loaded with phytochemicals, can enhance the therapeutic efficacy of active molecules through improved bioavailability and targeted delivery. This review summarizes the most current advanced applications combining phytochemicals and nanoformulations with promising wound healing potential. Various nanosystems loaded with phytochemicals have been identified, such as silver nanocarriers, zein-based nanoparticles, and various known polymers, which can be utilized to develop electrospun fibrous structures loaded with phytoremedies. Despite the incorporation of these remedies into traditional medicine for a long time, further clinical studies are essential to determine their pharmacological properties, safety concerns, and therapeutic efficacy.

1. Introduction

Wound healing represents a dynamic and highly complex biological process, which is vital for tissue homeostasis and skin integrity restoration after damage. Indeed, the skin, as the largest organ in the body, represents the main physical barrier against environmental consequences such as dehydration, mechanical trauma, and microbial invasion. The initiation of a series of complex biological events occurs to restore tissue integrity and function when this barrier is damaged [1]. Although wound healing is generally effective in most healthy individuals, abnormal pathological states, as well as external stressful factors, can cause wounds to become either acute or chronic during the healing process. Chronic wounds, usually defined as those that have not healed in 4–6 weeks, consume substantial healthcare resources, including treatment for infections, extremely long hospital stays, and high treatment costs [2]. Physiological wound healing has four overlapping but distinct phases, as follows: hemostasis, inflammation, proliferation, and remodeling. These phases are orchestrated by coordinated communication between immune cells, keratinocytes, fibroblasts, endothelial cells, and the extracellular matrix [3]. However, factors such as oxidative stress, ischemia, microbial contamination, advanced age, and systemic disorders such as diabetes can modify or delay the normal healing process [4]. The increasing prevalence of multidrug-resistant (MDR) infections has disrupted the treatment landscape and increased the demand for new and improved therapeutic strategies [5].

Phytochemicals are bioactive compounds derived from plants that have recently gained attention with regard to their possible roles in regulating the process of wound healing. Herbal extracts have been historically used for the treatment of wounds in indigenous medicine systems, and recent studies have proven phytochemicals to be highly effective in promoting tissue regeneration, lowering inflammation, reducing oxidative stress, and demonstrating strong antibacterial activity [6]. Aloe vera, honey, calendula, and chamomile are a few examples of herbal and natural items that have been used traditionally to enhance the healing of wounds [7].

In recent years, the simultaneous application of modern and traditional medicine, or ethnopharmacology, has been adopted by a vast majority of clinicians due to the adverse effects of the modern approach and synthetic drugs. Several phytochemicals and their effects on wound healing and skin regeneration have been studied, thereby establishing their clinical potential [7]. Ethnopharmacological methods likewise testify to the healing potential of plant species that are less known to the general public. For instance, many plant species have been used in the traditional treatment of wounds, exhibiting antioxidant, anti-inflammatory, anti-biofilm, and immunomodulatory activities [8]. These characteristics are crucial for the all-encompassing treatment of chronic wounds. Likewise, extracts high in flavonoids from Dactyloctenium aegyptium [9] have demonstrated positive outcomes in in vivo wound models, indicating their possible incorporation into contemporary medicinal formulations. Notably, species such as Curcuma aromatica, Cycas thouarsii, and Acmella oleracea have demonstrated remarkable wound healing properties through a variety of mechanisms [8]. Many phytochemical agents, including flavonoids, terpenoids, tannins, alkaloids, and phenolic acids, are known for their contributory effects to various aspects of tissue healing. For example, methanolic extracts from Acmella oleracea have been found to possess broad-spectrum antibacterial activity, enhance fibroblast migration, and significantly reduce the production of pro-inflammatory cytokines (TNF-α and IL-6) [6]. Regarding diabetic wounds, it was shown that the n-butanol fraction of Cycas thouarsii decreased matrix metalloproteinase-9 activity while increasing transforming growth factor β1 (TGF-β1) levels, suggesting that the extract might act both in collagen remodeling and anti-inflammatory action. Thus, even though phytochemicals are known to show exciting biological activities, in many cases, they have not found any therapeutic applicability, since they suffer from rapid metabolism, low bioavailability, poor solubility in water, and instability under physiological conditions [10]. New developments focus on the use of nanotechnology-based delivery systems to deliver phytochemicals and overcome these limitations to their therapeutic efficiency [11].

Nanotechnology solutions provide more efficient wound care due to improved drug solubility, prolonged release, site-specific targeting, and the co-delivery of drugs. Hydrogels, electrospun nanofibers, nanoparticles, and quantum dots have been utilized as effective platforms for the entrapment of phytochemicals [12]. These systems increase cellular uptake and the therapeutic index of active substances while simultaneously protecting them from degradation [13]. Poly(vinyl alcohol)- (PVA) nanofibers incorporated with flaxseed extract exhibited superior wound healing compared to control groups, with a significantly higher wound closure of 97.3% and antimicrobial activity against both Gram⁺ and Gram⁻ bacteria [14]. Another study showed that rosmarinic-acid-loaded CS/polyethylene oxide nanofibers enhanced α-smooth muscle actin and elastin expression, thereby expediting wound contraction and supporting tissue regeneration in diabetic mice [13]. Inorganic nanoparticles have also been applied as possible carriers for enhanced wound healing; carbon-based quantum dots are becoming the next-generation nanomaterials for wound care because of their intrinsic antibacterial activity, photostability, and theranostic potential, which surpass even conventional nanoparticles. Moreover, their antibacterial activity is enhanced by functionalization with phytochemicals or doping with elements like sulfur or nitrogen potentially involved in combating MDR microorganisms commonly associated with chronic wound infections [15].

On the one hand, there seems to be a paradigm shift in wound care with the combination of phytotherapy with nanotechnology to provide treatment solutions that acknowledge the intricate wound pathophysiological mechanisms at play. Nevertheless, the clinical validation, regulatory approval, large-scale production, and standardization of these cutting-edge treatments continue to pose challenges [16]. In this context, the aim of this review article is to summarize the most current research findings on nanotechnology-based formulations employing phytochemicals known to provide wound healing properties. A thorough search was conducted on databases such as PubMed^®, ScienceDirect^®, and Google Scholar^® from 2020 to 2025 using keywords such as wound healing, infections, phytochemical, nanofibers, and nanoparticles. The main inclusion criteria were studies involving the previous terms and especially “Wound AND Healing OR Infections AND nanoparticles OR nanofibers”. The number of articles retrieved using the main inclusion keywords is shown in Figure 1. In addition, an introductory section about the stages of wound healing is also included so readers can understand how phytochemicals can play a significant role in wound healing.

2. Phytochemicals with Wound Healing and Antimicrobial Efficacy

Phytochemicals have historically been used to treat wounds, and they continue to be commonly employed in various therapeutic approaches because of their accessibility, biocompatibility, and multiprolonged activity. Phytochemical compounds are substances that naturally exist in plants. They are important for controlling inflammation, preventing infection, and accelerating wound healing. Each step of wound healing is associated with a variety of biological functions exerted by secondary metabolites, such as flavonoids, tannins, saponins, glycosides, phenolic acids, terpenoids, and alkaloids [17,18]. Flavonoids, widely available in plant extracts, are associated with free radical scavenging, the inhibition of lipid peroxidation, and alterations in many signaling pathways that govern inflammatory responses [19]. By offering antioxidant protection, anti-inflammatory modulation, antibacterial action, and encouragement of tissue regeneration, phytochemicals have shown the capacity to intervene at several points in this sequence [20].

Various phytochemicals might disrupt bacterial membranes or inhibit microbial enzymes, as follows: saponins, tannic acid, alkaloids, and berberine. Such effects have proven very useful against wound-infecting bacteria like Pseudomonas aeruginosa and Staphylococcus aureus [21,22]. Moreover, elevated levels of ROS signify oxidative stress, which interferes with wound healing via cell injury and the destruction of ECM proteins. Many phytochemicals scavenge the ROS produced, thus maintaining cell integrity during the healing process. On the contrary, curcumin and chlorogenic acid have been shown to improve angiogenesis in wound healing through their ability to lower oxidative damage and improve fibroblast viability. Notably, many phytochemicals, such as those derived from honey and curcumin, mainly switch off pro-inflammatory mediators such as TNF-α. Figure 2 depicts how inflammation is reduced by honey and curcumin through the inhibition of TGF-β1, MMPs, and inducible nitric oxide synthase (iNOS), leading to reduced oxidative stress, reduced ECM degradation, and reduced fibroblast hyperproliferation, which are commonly seen in chronic wound pathology and hypertrophic scar formation. The anti-inflammatory and ECM-stabilizing functions of tannic acid from Terminalia arjuna and chebulagic acid from Terminalia chebula follow the same pattern. These phytochemicals promote keratinocyte and fibroblast proliferation and facilitate angiogenesis through VEGF overexpression [20].

The healing abilities of many traditional plants have been confirmed in recent studies; for example, Sphagneticola trilobata contains flavonoids, alkaloids, and terpenoids and has been found to cause fibroblast proliferation and collagen synthesis in vitro. In excision wound models, it significantly reduced TNF-α while increasing collagen and smooth muscle actin levels, indicative of anti-inflammatory and regenerative properties [23]. It also possesses additional high flavonoid, tannin, and phenolic contents that grant Senna auriculata its antibacterial and wound-healing properties. Its methanolic extract possesses strong antioxidant and anti-inflammatory effects and efficacy against several bacterial species, such as Staphylococcus aureus and Bacillus subtilis [24]. Another study evaluated the wound healing properties of Malva parviflora in excisional wound models, showing that its ethanolic leaf extract, rich in flavonoids and polyphenols, improved antioxidant status, increased collagen and hydroxyproline content, and facilitated wound healing [25]. In general, phytochemicals are a treasure trove of medicinal agents for healing wounds, making them excellent candidates for developing novel therapeutic options, owing to their diverse effects at all wound-healing progression stages, including antioxidant, antibacterial, anti-inflammatory, and regenerative activities.

3. Wound Healing Phases

The wound healing process has been widely discussed in the literature; in brief, four stages (Figure 3) have been identified in the wound healing process, known as hemostasis, inflammation, proliferation, and remodeling [26]. After injury of the lymphatic vessels, leading to hemorrhage, blood clotting occurs through the clotting cascade and thrombocyte aggregation by exposed collagen during the hemostasis phase [27]. Simultaneously, platelets decrease blood flow via vasoconstriction, reducing the gaps between tissue points [1,28]. The formed clot is composed of growth factors, fibrin, fibronectin, fibroblasts, and other molecules that create a matrix. The inflammation phase, occurring in two to five phases, is important, since it disinfects the wound with the emergence of neutrophils. These neutrophils have the ability to phagocytize and release proteases (e.g., elastase), which help to remove any debris or residues and break down the bacteria. Moreover, to enhance the inflammatory phase, neutrophils produce mediators (TNF-α, IL-1, and IL-6) that trigger VEGF and IL-8. Furthermore, the presence of macrophages stimulates inflammation, eliminates apoptosis, and encourages cell growth and tissue healing [29]. During the inflammatory phase, edema, erythema, and pain are common symptoms. The next stage, proliferation, is the most significant phase, lasting from six to twenty-one days [30]. During this phase, the wound heals by the formation of new collagen and extracellular matrix tissue. As days pass, the wound reduces in size and new tissues develop. New blood vessels are required so that the granulation tissue receives oxygen and nutrients. Moreover, fibroblasts differentiate into myofibroblasts, connecting the margins of the wound, giving the granulation tissue a pink to red appearance. Additionally, the wound is resurfaced by epithelial cells, with healing accelerated by the presence of moisture. Finally, tissue restoration can occur from collagen [31]. Tissue remodeling—the last phase of the wound healing process—can continue for months or even years, despite the fact that clinicians consider wound closure as the end of wound healing [32]. The remodeling phase process determines scarring and wound recurrence; this phase involves neovascular regression, extracellular matrix deposition, and the transformation of granulation tissue into scar tissue. Although collagen type III comprises the granulation tissue, a stronger type, collagen I, replaces it [33]. The scar tissue and duration of healing at this stage depend on many factors, such as the location of the wound, possible microbial colonization, and severity and treatment. In most cases, the new tissue gradually obtains mechanical strength and flexibility. However, sometimes wounds cannot completely heal, and, therefore, treatment is quite crucial. The use of active molecules and proper dressings can enhance the wound healing process, reducing hospitalizations and incidents such as bacteremia, fungemia, and even death [34].

4. Factors Affecting Wound Healing Process

Wound healing arises from both local and systemic factors; local influences directly affect wound characteristics, whereas systemic conditions—reflecting overall health and disease status—indirectly modulate the repair process. These interrelated mechanisms underscore the complexity of the wound healing process [35].

4.1. Local Factors Influencing Wound Healing

4.1.1. Oxygenation

Vascular disruption and high oxygen consumption in early wounds result in marked hypoxia due to reduced tissue oxygenation. Systemic factors like aging and diabetes further impair vascular flow, exacerbating the hypoxic state. This deficiency in oxygen supply is central to the pathophysiology of hypoxic and chronic wounds, as transcutaneous measurements indicate tissue oxygen tensions of 5–20 mm Hg in chronic wounds compared to 30–50 mm Hg in healthy tissue [36].

Key contributors to wound hypoxia include peripheral vascular diseases that limit oxygen delivery, increased oxygen demand from healing tissue, and ROS production via respiratory burst and redox signaling. Additional factors—such as arterial hypoxia from conditions like pulmonary fibrosis, pneumonia, sympathetic pain responses, hypothermia, anemia, cyanotic heart disease, or a high altitude—can further vary the degree of wound hypoxia, ranging from near-anoxia to moderate levels [37].

ROS are pivotal regulators of wound healing, exerting antimicrobial effects, modulating immune signaling, and promoting angiogenesis, cell proliferation, and extracellular matrix formation. In particular, hydrogen peroxide (H₂O₂) plays a key role. However, dysregulated ROS levels due to excessive production or insufficient detoxification can lead to oxidative stress, impairing healing and contributing to chronic wound development, while also supporting endothelial function through HIF-1α stabilization and VEGF signaling [38].

Excess ROS prolong inflammation, promote infection, and disrupt cellular signaling, thereby contributing to chronic wound pathogenesis. Preclinical strategies include antioxidants (N-acetyl-L-cysteine), enzymes (superoxide dismutase), biocompounds (Resolvin E1), and nanomaterials (cerium oxide nanoparticles) to balance oxidative stress. Oxygen therapies, both topical and hyperbaric, further reduce hypoxia and accelerate healing [39].

4.1.2. Infections

A biofilm provides bacteria with enhanced survival capabilities absent in planktonic states by establishing a protective niche with favorable physicochemical conditions. This structure confers a 1000–1500 times greater resistance to antibiotics and promotes robust bacterial colonization and persistence by facilitating nutrient intake and waste disposal through a rudimentary circulatory system [40]. Biofilm bacteria employ gene transfer and quorum sensing to enhance protection, facilitate intercellular communication, and promote beneficial species. These mechanisms, combined with regulated gene expression, contribute to robust antibiotic resistance, leading to persistent, chronic wounds. Despite modern investigative techniques, biofilm adaptability and environmental attachment continue to challenge the effective management of recalcitrant wounds [41]. The literature identifies E. faecium, S. aureus, K. pneumoniae, A. baumannii, P. aeruginosa, and Enterobacter spp. as predominant bacteria in chronic wound biofilms, with coagulase-negative staphylococci and Proteus spp. also implicated. Notably, fungal species, particularly Candida, are emerging as significant contributors [42,43]. Polymicrobial biofilms in chronic wounds exhibit synergistic interactions that transform non-virulent bacteria into virulent strains, enhancing biofilm biomass and functionality, ultimately contributing to host tissue damage [41].

4.2. Systemic Factors That Influence Healing

4.2.1. Age

Aging significantly impairs wound healing by prolonging inflammation, increasing oxidative stress, and causing inefficient microcirculation [44]. Enhanced platelet adherence elevates pro-inflammatory cytokine release, recruiting neutrophils but reducing monocyte infiltration due to decreased endothelial adhesion molecule expression. This impairs macrophage maturation, limiting angiogenesis, collagen production, and the resolution of inflammation [45]. Prolonged inflammation elevates ROS, causing tissue damage, apoptosis, senescence, and the disruption of proliferative healing phases. Additionally, aged skin suffers from impaired microcirculation, reducing the delivery of oxygen, nutrients, and inflammatory mediators, causing hypoxia and cellular death, which further prolongs the healing process. Collectively, these factors significantly delay and complicate wound healing in elderly individuals [46].

4.2.2. Sex Hormones

Wound healing can also vary according to gender; for example, while dermal wounds typically heal quicker in females, oral mucosal wounds demonstrate a male advantage in healing rates. This discrepancy suggests a tissue-specific influence of sex hormones on wound healing. Estrogens and progesterone modulate mucosal inflammation, impacting gingivitis and periodontal disease, but their direct role in mucosal wound healing remains unverified [47]. In dermal wounds, androgens tend to prolong healing by suppressing inflammation, whereas estrogens expedite the process [35,48]. Conversely, mucosal wounds heal more rapidly, with minimal inflammation and scarring, indicating that lower inflammatory responses may be optimal. Women generally exhibit stronger immune responses, attributed to hormonal differences, particularly lower androgen levels. Testosterone’s immunosuppressive effects contrast with its pro-inflammatory role in dermal wounds, while estrogens generally exert anti-inflammatory properties [47].

4.2.3. Stress

Chronic stress, such as caregiving for dementia patients, has been associated with significant immune dysregulation, resulting in delayed wound closure. Specifically, studies demonstrate reduced IL-1β expression, a critical cytokine involved in the inflammatory response to tissue injury. Similarly, acute stressors, including academic examinations and marital conflict, impair wound healing by suppressing key pro-inflammatory mediators such as IL-6, IL-1β, and TNF-α [49]. Animal models further elucidate the underlying mechanisms involved, showing that the stress-induced elevation of glucocorticoids inhibits the recruitment of inflammatory cells, impairs bacterial clearance, and prolongs wound healing. Moreover, increased cortisol levels correlate with delayed healing in humans, highlighting the endocrine system’s role in this process. Clinical and observational studies reinforce these findings, demonstrating that heightened psychological distress predicts slower recovery from surgical wounds and naturally occurring skin ulcers [50,51]. Furthermore, various studies highlight a link between occupation and stress levels, which eventually can lead to delayed wound closure. For example, shift work, disturbed sleep patterns, long working hours, insufficient personal time with family, and an unhealthy diet due to extended hours can all affect mental health and increase stress levels. Job “burnout” can affect wound care management, and physicians should consider recommending sick leave during the wound healing process, which may benefit patients [52].

4.2.4. Diabetes and Other Autoimmune Diseases

Diabetes induces a hyperglycemic environment, disrupting the normal phases of wound repair. This disruption prolongs inflammation, compromises angiogenesis, and hinders collagen synthesis, resulting in chronic non-healing wounds [53]. Hyperglycemia exacerbates oxidative stress, contributing to the sustained activation of pro-inflammatory cytokines and impaired function of critical wound-healing cells, including macrophages, neutrophils, fibroblasts, and keratinocytes. Specifically, diabetic wounds exhibit dysfunctional macrophage polarization, the attenuated production of growth factors like VEGF, PDGF, and TGF-β, and elevated matrix metalloproteinase (MMP) levels. Elevated MMPs degrade extracellular matrix proteins excessively, impairing wound closure [54]. Microvascular complications due to diabetes cause local ischemia and hypoxia, further delaying wound repair by reducing nutrient and oxygen supply. Advanced glycation end-products (AGEs) formed during chronic hyperglycemia interfere with collagen deposition and induce inflammatory responses, amplifying tissue damage and delaying healing [55].

Another systemic factor affecting wound healing is autoimmune diseases. In individuals with immune system disorders, the wound healing process is significantly prolonged [56]. Ulceration and recurrent leg ulcers are commonly seen in autoimmune diseases such as rheumatoid arthritis and lupus. The prolonged healing time in these patients increases the risk of infection [57].

4.2.5. Obesity

Obesity is a serious condition that is becoming increasingly prevalent worldwide. In individuals diagnosed with obesity, increased adipose tissue is often accompanied by hypoperfusion, which can lead to ischemic symptoms [57]. Adequate oxygenation of the tissue is critically important during the wound healing process. The hypoperfusion observed in obese individuals increases the risk of infection in the wound area [58].

4.3. Medications

4.3.1. Glucocorticoid Steroids

Glucocorticoids (GCs) are extensively utilized in the management of various pathological conditions due to their potent anti-inflammatory activities [59]. However, despite this therapeutic efficacy, GC administration is linked to significant adverse effects, notably impaired wound healing [60]. This impairment occurs through the transrepression of pro-inflammatory cytokines, growth factors, matrix proteins, and matrix proteases, or via the direct suppression of genes essential for tissue restoration [61]. While systemic corticosteroids exert inhibitory effects on wound repair, topical corticosteroid therapy demonstrates a distinct pharmacological profile. Low-dose topical corticosteroids have been shown to enhance wound healing, alleviate pain and exudate, and prevent excessive granulation tissue formation in approximately 79% of cases. Despite these beneficial outcomes, the prolonged application of topical corticosteroids necessitates careful clinical monitoring to mitigate the potential risk of increased susceptibility to infection [62].

4.3.2. Non-Steroidal Anti-Inflammatory Drugs

Non-steroidal anti-inflammatory drugs (NSAIDs) are frequently utilized for their anti-inflammatory, analgesic, antipyretic, and antithrombotic effects. By suppressing prostaglandin synthesis and modulating arachidonic acid metabolism, NSAIDs influence multiple inflammatory pathways. However, they seem to impair wound healing by reducing keratinization, epithelialization, angiogenesis, and granulation [63]. Conversely, short-term use may enhance wound repair in specific settings, and aspirin has demonstrated efficacy in promoting chronic wound healing via anti-inflammatory modulation [64].

4.3.3. Alcohol Consumption

Alcoholism is a serious public health issue because of its association with elevated global mortality rates. Chronic alcohol consumption is recognized as a risk factor that impairs tissue repair by increasing susceptibility to infections and suppressing both innate and adaptive immune responses [65,66]. Clinical and preclinical studies indicate that alcohol exposure delays wound healing and heightens infection risk [35]. Moreover, alcohol-induced oxidative stress leads to ROS formation, contributing to cellular morphological and functional deterioration. Acute alcohol exposure disrupts the proliferation phase by inhibiting cell proliferation and angiogenesis via reduced proangiogenic factor synthesis. Additionally, alcohol toxicity promotes elevated matrix metalloproteinase-8 (MMP-8) and plasmin levels, accelerating fibrin degradation, diminishing fibroblast function, and impairing collagen synthesis, thereby prolonging wound closure [67].

4.3.4. Smoking

Tissue hypoxia significantly disrupts wound healing, particularly in smokers, due to reduced oxygenation and impaired immune function. Hypoxia increases infection risk by diminishing neutrophil bactericidal activity, with cigarette smoking recognized as a major contributor to impaired wound repair [68].

Nicotine-induced vasoconstriction reduces blood flow, while carbon monoxide binds to hemoglobin, limiting oxygen transport. Hydrogen cyanide disrupts cellular respiration. Smoking also inhibits erythrocyte, fibroblast, and immune cell function, compromising collagen synthesis and angiogenesis. These effects collectively hinder wound closure and tissue regeneration [69].

4.3.5. Nutrition

Calcium and vitamin K are crucial for initiating and regulating the coagulation cascade, thereby enabling fibrin clot formation during inflammatory processes. Moreover, these nutrients play key roles in the post-translational modification of proteins essential for coagulation and bone metabolism [70]. Vitamin A significantly contributes to the initial inflammatory response by promoting macrophage, monocyte, and fibroblast migration [71]. Vitamin E exerts important anti-inflammatory effects and plays a key role in maintaining the integrity of cellular membranes. Zinc is pivotal in modulating the immune response [72]. Proteins such as arginine and glutamine are essential for immune function and actively support tissue regeneration and repair. Lipids are important due to their anti-inflammatory properties, as they provide essential energy substrates and protect cellular structures [73]. Amino acids become particularly vital during the proliferation phase of wound healing. Arginine supports collagen synthesis, enhances neovascularization, and facilitates wound contraction [74]. The vitamin B complex significantly contributes to metabolic processes and actively promotes cellular proliferation. Lipids supply the energy required for wound healing and proliferation, serving as structural elements for epidermal and dermal tissues, and are critical in synthesizing cellular membranes and forming the intracellular matrix. Zinc significantly contributes to cellular proliferation, aiding in wound reconstruction. Iron is crucial for hemoglobin production, ensuring adequate tissue oxygenation during the wound healing process, and plays a role in collagen synthesis [35]. Vitamin C is essential for collagen synthesis, whereas vitamin E helps to reduce scar formation. Zinc serves as a critical cofactor in collagen synthesis, facilitating collagen maturation. Lastly, water, although frequently overlooked, plays a fundamental role in tissue healing by aiding epidermal cell mobility and maturation, as well as providing critical structural support within the cytoplasm of skin cells [74].

5. Nanoformulations for Wound Healing

Formulations based on nanotechnology are widely investigated as effective drug delivery systems for a variety of diseases and infection control. Nanocarriers have shown promising properties, since they can be used to enhance drug solubility, enable controlled and sustained drug release, chemically or physically stabilize therapeutic agents, and achieve higher drug concentrations at target sites because of the Enhancement Permeability and Retention (EPR) effect. Moreover, when topically applied, drug-loaded nanoparticles can often accumulate in hair follicles, thereby facilitating the permeation of drug molecules through the stratum corneum and releasing them into the deeper layers of the skin. The most used nanoformulations for wound healing and infection control are polymeric and inorganic nanoparticles, lipid nanoparticles, and nanofibers, which can be further entrapped in wound dressings so to enhance their performance. Herein, polymeric and inorganic nanoparticles and other nanoformulations loaded with phytochemicals are discussed. Additionally, wound dressings based on electrospun nanofibers entrapping phytochemicals are also discussed.

5.1. Electrospun Nanofibers Loaded with Phytochemicals

Antibacterial wound dressings can be developed through various techniques such as phase separation [34], solvent casting [75], and electrospinning [76]. The electrospinning process is a widely used and versatile technique, which can produce fibrous and nanofibrous dressings [77] with a high surface to volume ratio and tunable mechanical properties. Their fibrous nature resembles the extracellular matrix enhancing cellular adhesion, proliferation, and differentiation, and, therefore, nanofibrous wound dressings have been extensively examined [78].

During the electrospinning process, a polymeric solution using biocompatible and/or biodegradable natural (i.e., chitosan (CS), hyaluronic acid (HA), alginic acid (AA), and gelatin (Gel)) or synthetic macromolecules (poly(lactic acid)-PLA, poly(lactic-co-glycolic acid)-plga, pol(vinyl pyrrolidone (PVP), and poly(vinyl alcohol-PVA)), is injected through a syringe equipped with a needle. The droplet that forms at the tip of the needle obtains a cone shape due to the applied voltage—known as a Taylor cone. When the Taylor cone is obtained, the fibers are collected on the metallic collector (drum or plate), creating a randomly or aligned oriented nanofibrous matrix (Figure 4).

Throughout the literature, various wound dressings based on electrospun nanofibers have been identified, revealing interesting results with the potential to be clinically translated. Nanofibers are reportedly superior to various dressings such as cotton, gauze, sponge, hydrocolloids, and hydrogels [79]. They have a three-dimensional structure, increased porosity, surface with improved gas exchange, water vapor permeability, and enhanced active molecule delivery Electrospun wound dressings can incorporate antimicrobials, synthetic drugs, and growth factors to improve wound healing and minimize wound infections [28,29]. However, in recent years, the incorporation of phytochemicals, natural substances, and extracts from plants into nanofibrous dressings has been shown to improve tissue regeneration, modulate inflammation, and increase cost-effectiveness [20]. PVA is a semi-crystalline synthetic polymer. Due to its biodegradability, its major applications are in drug delivery, wound dressings, and as a scaffold for tissue regeneration. PVA-based wound dressing materials have increasingly attracted attention because of their many properties, including affordability, non-toxicity, biodegradability, and biocompatibility. An antibacterial scaffold based on PVA nanofibers loaded with flaxseed ethanolic extract was developed via electrospinning. Various ratios of flaxseed and PVA were studied, and the most optimal ratio was the 30% extract. Flaxseed, commonly known as Linum usitatissimum, has been used to improve digestion, but has also shown other remarkable health effects. Herein, the authors concluded that the flaxseed extract PVA dressing inhibited the growth of Salmonella Typhimurium, Escherichia coli, Staphylococcus aureus, and Pseudomonas aeruginosa while improving wound healing [14].

Mouro et al. developed electrospun wound dressings based on PLA, PVA, and chitosan (CS) entrapping Hypericum perforatum L. The technique used herein was emulsion electrospinning. The fibrous matrices (Figure 5) exhibited promising properties for wound dressings because of their porous morphology, which was similar to the extracellular skin matrix and its swelling index, wettability, and water vapor transmission rate. Finally, the cytocompatible wound dressings displayed the inhibition of S. aureus growth, which is an important parameter for wound healing [76].

In the last decade, chitosan, a natural biopolymer originating from the deacetylation of chitin and obtained from fungi, crustaceans shells, and insects, has been explored as a potent drug carrier due to its hydrophilicity, swelling ability, biocompatibility, and potential to functionalize with other polymers. CS has been identified as one of the most promising biopolymers for medical devices and implants, tissue engineering, and drug delivery applications [80,81,82,83,84]. Baicalein (BAC) is a herbal compound with both antioxidants and antimicrobial effects, originating from Scutellaria baicalensis Georgi; to reinforce its activity, BAC-modified CS was molded into nanofibers via the electrospinning process and studied for its wound healing potency. From the results, the electrospun nanomats presented desirable antioxidant and antimicrobial properties, which improved the wound healing process. These nanomats can promote wound healing while meeting clinical standards due to their mechanical properties. Furthermore, the grafting process improves the solubility of CS, which is important for drug delivery applications [85].

Figure 5. The fibrous morphology of wound dressings based on PLLA, PVA, and chitosan (CS), with and without Hypericum perforatum L. (HP). SEM micrographs and diameters of PLLA/PVA/CS wound dressings without HP extract, with 2.5% HP extract, and with 5% HP extract. Reprinted under open access Creative Common CC BY License, MDPI (2023) [82].

Figure 5. The fibrous morphology of wound dressings based on PLLA, PVA, and chitosan (CS), with and without Hypericum perforatum L. (HP). SEM micrographs and diameters of PLLA/PVA/CS wound dressings without HP extract, with 2.5% HP extract, and with 5% HP extract. Reprinted under open access Creative Common CC BY License, MDPI (2023) [82].

Most frequently, CS is mixed with other polymers to present improved properties. Royal jelly, a honeybee secretion, exhibits various biological activities and important antibacterial and anti-inflammatory properties; therefore, Yu et al. developed nanofibrous dressings based on PVA/CS impregnated with royal jelly. Nanofibers with sizes of around 200–300 nm demonstrated hydrophilicity and vapor permeability, significant parameters for wound healing. Furthermore, the royal-jelly-loaded nanofibers were able to halt the microbial growth of Staphylococcus aureus and Escherichia coli. Given their improved antibacterial performance, these nanofibrous dressings have great potential in combating wound infections [86]. Similar wound dressings of PVA/CS were designed by electrospinning to inhibit infection and promote healing. The authors examined extracts from Thymus vulgaris and Zingiber officinale incorporated into a nanofibrous mat with a diameter size of around 380 nm. The fabricated dressings demonstrated a porous surface, enhanced wettability properties, and liquid absorption capacity. Moreover, the nanofibers exhibited antioxidant properties and increased antibacterial activity against S. aureus and E. coli strains, while promoting wound healing in bacteria-infected rats [87]. Electrospun bilayer nanofibers comprising a CS/PVA active layer and PCL inactive back layer were fabricated to analyze the potential of pomegranate flower extract delivery. Nanofibrous dressings with diameter sizes of around 400 nm exhibited liquid absorption characteristics, wound healing effects, and, most significantly, antimicrobial performance against strains of S. aureus and P. aeruginosa. The extract-loaded nanofibers showed accelerated wound healing of almost 88% within two weeks [88]. Alginic acid (ALG) and its derivatives are widely used for wound healing and anti-infective systems, since they have been found to be effective against microbial growth inhibition. Therefore, to enhance its physicomechanical properties, ALG has been blended with various polymers. In a recent study, nanofibrous mats from PVA and ALG loaded with natural extracts from Lawsonia inermis (LI) and Scrophularia striata (SS) were studied for their wound healing potency. The biocompatible matrices exhibited antimicrobial activity, especially those with the extracts. Furthermore, in vivo studies demonstrated that the nanofibers promoted wound healing and tissue regeneration [89]. Chlorogenic acid is 5-caffeoylquinic acid, widely found in fruits, vegetables, and plants, exhibiting anti-inflammatory, antidiabetic, and wound healing properties, among others. In an interesting study, chlorogenic acid was loaded into dopamine (DA)-functionalized alginate (Alg-DA) conjugates and further impregnated into innovative wound dressings based on PVA. The nanofibrous mats displayed improved water absorption, a desirable water vapor transmission rate, and porous morphology, as well as a hydrophilic nature. Additionally, the biocompatible nanofibrous matrices showed antibacterial activities, improved antioxidant activity, and can effectively protect cells from oxidative damage. Finally, the multifunctional wound dressings showed the promotion of wound healing and could be a promising solution for wound healing and the management of wound infections [89]. Poly(ε-caprolactone)-PCL, a semi-crystalline synthetic polymer, is frequently utilized in tissue engineering applications owing to its biocompatibility and biodegradability, as well as desirable mechanical properties. The combination of PCL as a layer in bilayer wound dressings is well-studied. Therefore, PCL/PVA-CS nanofibrous dressings entrapping an ethanolic leaf extract of Tridax procumbens L. were examined for their antibacterial and tissue regeneration effects. The biocompatible nanofibers (studied using the L929 cell line) exhibited a greater inhibition of E. coli than S. aureus, as well as improved wound healing in biopsy punch wounds and laser burns [90]. An electrospun nanofibrous mat with a top layer of PCL–silk sericin and bottom layer of chitosan–alginate hydrogel was studied for its possible use in combating wound infections. The inner layer was loaded with 10-hydroxydecanoic acid (10-HDA), known as queen bee acid, an anti-inflammatory, antibacterial, and immunomodulatory agent. In vitro and in vivo studies revealed that the top layer exhibited a normal swelling index with protection against microbes, compared to the hydrogel-based layer, which demonstrated increased swelling and rapid healing. Interestingly, even 1% 10-HDA improved cell proliferation and antimicrobial activity. Finally, when the wound dressings were tested on Wistar rats, they enhanced wound healing without any inflammatory side effects, according to clinical and histological assessments combined with an analysis of their biophysical properties of skin healing [91]. Another nanofibrous wound dressing with multiple layers was developed, so as to mimic the skin structure; the top layer comprised a cellulose microfiber, while the bottom layer was made from pectin, soy protein isolate, and pomegranate peel extract. The bilayer nanofibrous mats exhibited notable mass loss in PBS solution and improved mechanical properties. The cytocompatible wound dressing demonstrated cell adhesion, angiogenesis, and rapid wound healing activity in vivo, being classified as a promising approach for clinical applications [92]. Hajati Ziabari et al. fabricated multilayered nanofibrous matrices composed of PCL and collagen incorporating Malva sylvestris extract, and an inactive layer with only PCL. The diameters of the fibers ranged from 120 to 140 nm, while the water vapor transmission values of the NFs could be compared to those of commercial dressings such as Tegaderm, Bioclusive, and Op Site. Additionally, the electrospun nanomats showed improved water uptake, which can be beneficial for wound exudate handling, while prolonging the release of the extract. The biocompatible nanofibers demonstrated hemocompatibility and rapid blood clotting, along with improved tissue regeneration [93]. Curcumin, a polyphenolic bioactive compound that is widely found in many plant species, most commonly in Curcuma longa, and berberine, a derivative of the parent molecule berberine, both demonstrate strong antibacterial activity against methicillin-resistant Staphylococcus aureus (MRSA). Therefore, Kandaswamy et al. examined the synergistic action of these phytochemicals when loaded into a PCL nanofibrous matrix. The nanofibers demonstrated an effective inhibitory potency against MRSA growth, along with improved mechanical properties, swelling ability, and thermal stability. The biocompatible mats, when studied in vivo in zebrafish models, exhibited rapid wound closure [94].

Oryzanol is a mixture of lipids originating from rice (Oryza sativa) and has numerous uses in the food and biomedical industries. The main problem of oryzanol comes with its low aqueous solubility and its photothermal stability. Cyclodextrin complexation is a known procedure to enhance the solubility of poorly soluble agents; in a recent study, oryzanol was encapsulated into modified β-cyclodextrin and further loaded into PCL-CS nanofibrous matrices. According to the results, cyclodextrin complexes of oryzanol demonstrated improved antibacterial and wettability properties, while the matrices showed tissue re-epithelialization and reduced inflammation [95]. Another study employed wound-healing nanofibrous dressings based on PCL and cellulose acetate (CA) as matrices to inhibit microbial growth and improve wound healing. The mats were further loaded with prinoides leaf, which is rich in many phytochemicals. It was revealed that the nanofiber-based mats, with a smooth morphology and fiber diameters of 330–380 nm, had antibacterial potential against S. aureus and E. coli. Furthermore, the PCL-CA mats improved cell migration to the wound area, while Rhamnus prinoides enhanced their hydrophilic nature and aqueous absorption [96]. Electrospun nanonets/mats based on PCL and collagen, fabricated with acetic acid and formic acid and loaded with propolis extract, were studied for their wound healing potential. Propolis extract is widely used due to its wound healing capability. The nanoscaffolds with fibers displayed diameters ranging from 164 to 728 nm, while the nanonets were around 20 nm. From the results, the water vapor transmission rate values of the nanofibers/nanonets were similar to commercial dressings such as Tegaderm. Additionally, the propolis-loaded NFNs showed strong cytoprotective effects, while the viability of HFF-2 cells rose considerably after 72 h. Furthermore, the nanomats’ hemocompatibility underscores their potential as treatments for wound healing [97]. Dihydromyricetin is a natural flavonoid derived from traditional Chinese medicines, i.e., Hovenia dulcis and Ampelopsis grossedentata, and has shown wound healing promotion due to its antioxidant, antimicrobial, and anti-inflammatory properties. Nonetheless, this flavonoid is hydrophobic and prone to degradation by limiting its use. Inclusion complexes of dihydromyricetin and hydroxypropyl-β-cyclodextrin were developed and further incorporated into electrospun mats based on a blend of pectin polysaccharides (PPs), CS, and PVA. The fibers presented diameters ranging from 200 to 400 nm, comprising an interconnected matrix similar to that of the skin. In addition, the bio- and hemocompatible nanofibrous mats demonstrated an improved hydrophilicity and wettability, while flavonoids were sustainably released from the mat. Finally, the mats loaded with the inclusion complexes exhibited great antioxidant activity and halted the growth of S. aureus and E. coli. In vitro and in vivo studies showed an enhanced wound healing process [98]. Moshfeghi et al. developed a wound dressing with two layers to improve the multifunctionality of the dressings; the inner, which was crosslinked with genipin and CaCl₂, was based on SA and gelatin hydrogel, containing Matricaria chamomilla L. extract and silver sulfadiazine as antibacterial agents, while the top surface layer was covered by electrospun polyacrylonitrile nanofibers. The mechanical and swelling properties of the dressings were improved, while the biodegradability, biocompatibility, and efficient antibacterial activity were also enhanced. Sustained release of the AgSD drug was found, while in vivo studies showed promoted wound healing [99]. Finally, electrospun wound dressings based on PLGA, poly(methyl methacrylate) (PMMA), collagen, and glycine and loaded with Syzygium cumini leaf extract were developed via electrospinning and examined for their in vivo wound healing potential. The nanofibers demonstrated strong antimicrobial properties against S. aureus, C. albicans, C. glabrata, and B.s cereus, as well as S. paratyphi and E. coli, while in vivo models showed an improved wound healing process [100].

At last, Stojko et al. fabricated electrospun dressings (with sizes ranging from micro to nano diameters) composed of PLGA and loaded with propolis (Figure 6). The biodegradable mats released propolis in a controlled manner, and when they were applied on skin burns, they promoted burn wound healing in a desirable way [101]. Table 1 summarizes the electrospun nanofibrous matrices, the materials were developed from, and the extracts.

Figure 6. In vivo burn wound healing using PLGA 85/15 and 5% propolis dressings to burn wounds before (A) and after 21 days of treatment (B); PLGA 85/15 and 10% propolis dressings application before (C) and after 21 days of treatment (D). Reproduced under open access Creative Common CC BY License MDPI 2020 [100].

Figure 6. In vivo burn wound healing using PLGA 85/15 and 5% propolis dressings to burn wounds before (A) and after 21 days of treatment (B); PLGA 85/15 and 10% propolis dressings application before (C) and after 21 days of treatment (D). Reproduced under open access Creative Common CC BY License MDPI 2020 [100].

Table 1. Applications of electrospun nanofibers loaded with phytochemicals.

Polymers Used for the Wound Dressings	Phytochemical/Plant/Extract	In Vivo Models	Ref.
PLLA/PVA/CS	Hypericum perforatum L.	No	[76]
PVA	Flaxseed extract (Linum usitatissimum)	No	[14]
Chitosan (CS)	Baicalein (Scutellaria baicalensis Georgi)	No	[85]
PVA/CS	Royal Jelly	No	[86]
PVA/CS	Thymus vulgaris, Zingiber officinale	Yes	[87]
CS/PVA-PCL bilayer	Pomegranate flower extract	Yes	[88]
PVA/Alginic Acid (ALG)	Lawsonia inermis, Scrophularia striata	Yes	[102]
PVA/DA-functionalized Alginate (Alg-DA)	Chlorogenic acid	Yes	[89]
PCL/PVA-CS	Tridax procumbens L. extract	Yes	[90]
PCL-Silk Sericin/CS-Alginate Hydrogel	10-Hydroxydecanoic acid (10-HDA)	Yes	[91]
Cellulose (Cel)/Pectin (Pec)/Soy Protein Isolate (SPI)	Pomegranate peel extract	Yes	[92]
PCL/Collagen	Malva sylvestris extract	Yes	[93]
PCL	Curcumin (Curcuma longa), Berberine chloride	Yes	[94]
PCL-CS	Oryzanol (Oryza sativa)	Yes	[95]
PCL/Cellulose Acetate (CA)	Rhamnus prinoides leaf extract	Yes	[96]
PCL/Collagen	Propolis extract	Yes	[97]
Pectin Polysaccharides (PP)/CS/PVA	Dihydromyricetin (Hovenia dulcis, Ampelopsis grossedentata)	Yes	[98]
Sodium Alginate (SA)/Gelatin (Gel) with PAN top layer	Matricaria chamomilla L. extract, silver sulfadiazine (AgSD)	Yes	[99]
PLGA/PMMA/Collagen/Glycine	Syzygium cumini leaf extract	Yes	[100]
PLGA	Propolis extract	Yes	[101]

Table 1. Applications of electrospun nanofibers loaded with phytochemicals.

Polymers Used for the Wound Dressings	Phytochemical/Plant/Extract	In Vivo Models	Ref.
PLLA/PVA/CS	Hypericum perforatum L.	No	[76]
PVA	Flaxseed extract (Linum usitatissimum)	No	[14]
Chitosan (CS)	Baicalein (Scutellaria baicalensis Georgi)	No	[85]
PVA/CS	Royal Jelly	No	[86]
PVA/CS	Thymus vulgaris, Zingiber officinale	Yes	[87]
CS/PVA-PCL bilayer	Pomegranate flower extract	Yes	[88]
PVA/Alginic Acid (ALG)	Lawsonia inermis, Scrophularia striata	Yes	[102]
PVA/DA-functionalized Alginate (Alg-DA)	Chlorogenic acid	Yes	[89]
PCL/PVA-CS	Tridax procumbens L. extract	Yes	[90]
PCL-Silk Sericin/CS-Alginate Hydrogel	10-Hydroxydecanoic acid (10-HDA)	Yes	[91]
Cellulose (Cel)/Pectin (Pec)/Soy Protein Isolate (SPI)	Pomegranate peel extract	Yes	[92]
PCL/Collagen	Malva sylvestris extract	Yes	[93]
PCL	Curcumin (Curcuma longa), Berberine chloride	Yes	[94]
PCL-CS	Oryzanol (Oryza sativa)	Yes	[95]
PCL/Cellulose Acetate (CA)	Rhamnus prinoides leaf extract	Yes	[96]
PCL/Collagen	Propolis extract	Yes	[97]
Pectin Polysaccharides (PP)/CS/PVA	Dihydromyricetin (Hovenia dulcis, Ampelopsis grossedentata)	Yes	[98]
Sodium Alginate (SA)/Gelatin (Gel) with PAN top layer	Matricaria chamomilla L. extract, silver sulfadiazine (AgSD)	Yes	[99]
PLGA/PMMA/Collagen/Glycine	Syzygium cumini leaf extract	Yes	[100]
PLGA	Propolis extract	Yes	[101]

5.2. Nanoparticles Loaded with Phytochemicals

Figure 7 summarizes the various categories of nanoparticles loaded with phytochemicals, targeting wound infections and promoting tissue healing.

5.2.1. Inorganic Nanocarriers

P. aeruginosa is the predominant pathogen associated with burn wound infections, leading to slower wound healing and the possible development of chronic wounds. Consequently, developing effective antimicrobial therapies that simultaneously accelerate wound recovery has become essential. In this context, a novel nanosystem was examined, using mesoporous silica-coated UCNPs (UCNPmSiO₂) as a drug delivery vehicle for curcumin and ceftazidime (CAZ). An F23 aptamer was used to create a dual-targeting functional cell membrane from pre-treated macrophage membranes (pM). The nanosystem exhibited a spherical morphology with a consistent particle shape and displayed a negative zeta potential. In vitro studies revealed the superior antibacterial activity of the nanosystem compared to traditional antibiotic treatments alone. Furthermore, the nanosystem was able to effectively inhibit and eradicate bacterial biofilms, achieving enhanced antibacterial selectivity and activity. Importantly, near-infrared light irradiation augmented these antibacterial and anti-biofilm properties via a photodynamic mechanism. In the mouse model of P. aeruginosa-infected skin wounds, the nanosystem successfully eliminated bacterial infections and notably promoted wound healing, without evident systemic toxicity. Thus, this study represents a promising and innovative targeted nanotherapeutic approach, particularly suitable for managing Pseudomonas aeruginosa-related skin wound infections [103]. Another study investigated the therapeutic efficacy of a hydrogel containing zinc oxide nanoparticles synthesized from Gliricidia sepium (Jacq.)-GSL Kunth. ex. Walp. leaf extract in diabetic wound management. The chromatographic analysis of the leaf ethanolic extract identified the following major bioactive constituents: apigenin-7-O-glucoside, kaempferol, and protocatechuic acid, all recognized for their anti-inflammatory effects. The prepared hydrogel incorporated both GSL ethanolic extract and zinc oxide nanoparticles, demonstrating controlled-release characteristics along with an optimal swelling capacity. In diabetic wound models, the nanoformulations significantly accelerated tissue repair, minimized cellular apoptosis, and effectively modulated inflammatory responses. These outcomes were supported by evaluations of wound morphology, healing progression, histopathological examinations, and immunohistochemical staining. Collectively, these results underscore the promising potential of the nanoproduct as an effective therapeutic agent for diabetic wound healing [104]. These findings were further validated by evaluating specific biomarkers involved in wound healing. Treatment resulted in a marked decrease in the levels of vascular cell adhesion molecule-1 and advanced glycation end-products (AGEs), both known to negatively impact wound repair. Simultaneously, there was a significant elevation in beneficial mediators, including the anti-inflammatory cytokine interleukin-10 (IL-10) and platelet-derived growth factor (PDGF), both critical for promoting tissue regeneration and angiogenesis. Overall, the evidence presented underscores the promising therapeutic potential of Gliricidia sepium-derived zinc oxide nanoparticles hydrogel (GSL ZnONPs HG) as an effective intervention to enhance diabetic wound healing through the modulation of inflammation and the stimulation of reparative growth factors [104]. Current wound dressings often demonstrate limitations such as rigidity, an insufficient mechanical integrity, a low porosity, adherence to wound surfaces, and a lack of antimicrobial properties, thereby restricting their clinical efficacy. To address these challenges, a microporous, antibacterial chitosan–sericin–nano zinc oxide (CS-SS-nZnO) nanocomposite was developed to provide an effective microbial barrier and enhance wound healing. The composite was synthesized through a solution-casting approach incorporating nano zinc oxide (nZnO) within a chitosan–sericin matrix. FTIR spectroscopy verified the integration of characteristic functional groups corresponding to chitosan, sericin, and ZnO nanoparticles. FE-SEM analyses revealed a semi-crystalline structure with an irregular surface topography, and dynamic light scattering confirmed the nanoscale hydrodynamic dimensions of the incorporated ZnO. The prepared CS-SS-nZnO composites exhibited substantial free radical scavenging capabilities, along with pronounced antibacterial activity. Furthermore, hemocompatibility tests indicated minimal erythrocyte lysis (only 1.6%), signifying an excellent biocompatibility with negligible hemolytic potential. In vivo evaluations using animal models demonstrated significant wound closure (96%) within 14 days post-treatment. Histopathological findings further supported the efficacy of the nanocomposite, displaying enhanced tissue regeneration characterized by the restoration of skin architecture, increased collagen deposition, and the regeneration of hair follicles. Collectively, these outcomes position the CS-SS-nZnO nanocomposite as a promising and clinically relevant alternative to conventional wound dressings, offering superior healing, infection control, and safety profiles [105]. Silver nanoparticles are widely utilized either as wound dressings or topically applied products due to their antibacterial activity. Historically, silver-based antimicrobial agents have been utilized extensively to enhance wound recovery. Juglans regia L. has long been recognized in traditional medicine for its potential in promoting wound healing. Therefore, an interesting study aimed to evaluate the wound-healing efficacy of biologically synthesized silver nanoparticles (AgNPs). Notably, the bioreduced AgNPs derived from Juglans regia L. pellicle extract demonstrated a superior particle uniformity. The therapeutic effects of AgNPs, pellicle extract (P), and AgNP/P were evaluated against the standard treatment, Solcoseryl^®, using both incision and excision wound models. The parameters assessed included skin-breaking strength, wound contraction, epithelialization duration, histological changes, and cytokine modulation. Both P and its bioreduced nanoparticles exhibited significant wound-healing capabilities. In the incision model, skin tensile strength following AgNP/P treatment closely approximated Solcoseryl^®, significantly surpassing chemically synthesized AgNPs. The epithelialization times for AgNP/P and Solcoseryl^® (16.0 and 15.3 days, respectively) showed no significant statistical difference. Furthermore, enhanced collagen deposition was observed, accompanied by distinct cytokine profiles, including reduced interleukin-1β and elevated tumor necrosis factor-alpha, reflecting diverse cellular maturation processes consistent with the histopathological findings. These results collectively suggest that bioreduced AgNP/P holds promising potential as an effective pharmaceutical candidate for advanced wound dressings [106]. Additionally, silver nanoparticles (AgNPs) synthesized using Acer tegmentosum extract were integrated into CS/alginic acid (AL) scaffolds to facilitate the healing of E. coli-infected wounds. The synthesized formulation displayed substantial antimicrobial efficacy against both Gram-positive and Gram-negative pathogens, alongside an excellent biocompatibility, as shown by a negligible toxicity toward red blood cells, hen’s egg chorioallantoic membranes, and non-cancerous NIH3T3 cells. In vivo testing indicated that CS/AL-AgNP treatment markedly improved wound recovery rates by enhancing collagen synthesis and normalizing hematological parameters in E. coli-infected wounds. Collectively, the obtained data highlight the therapeutic potential of CS/AL-AgNP scaffolds as an efficient biomedical platform for managing bacterial wound infections [107].

5.2.2. Polymeric Nanocarriers

Polymer-based nanocarriers are widely used in the pharmaceutical and tissue engineering fields due to their multifunctionality, biodegradability, and biocompatibility. CS as natural polymer has been used in wound dressings, as stated previously. Hordein is a prolamin glycoprotein found in barley with an optimal low toxicity, biodegradability, and biocompatibility. Quercetin, known for its antioxidant, anti-inflammatory, and antimicrobial activities, has therapeutic potential; however, its clinical application is limited by its low bioavailability and stability. To overcome these challenges, one study developed a novel multifunctional nanoplatform, employing a self-assembly strategy encapsulating quercetin within a hordein/chitosan matrix to significantly enhance its bioavailability and stability. The developed nanoparticles were spherical, uniformly dispersed nanoparticles averaging 435 nm in diameter and possessing a positive zeta potential. Furthermore, they exhibited an excellent physicochemical stability, low cytotoxicity, and effective antimicrobial properties against Staphylococcus aureus and methicillin-resistant Staphylococcus aureus. In a bacterial wound model, the nanoplatform significantly outperformed free quercetin by accelerating wound closure, efficiently eradicating bacterial populations, mitigating inflammatory responses, scavenging ROS, and enhancing collagen synthesis and angiogenesis. Collectively, these findings highlight quercetin-loaded nanoparticles as a promising non-antibiotic therapeutic candidate for combating drug-resistant wound infections, warranting further investigation aimed toward clinical translation [108]. Zein, a natural biopolymer, exhibits excellent pharmaceutical properties, particularly advantageous for topical formulations. Moringa oleifera contains numerous phytopharmaceutical constituents, and its leaves have traditionally been utilized for promoting wound healing. This study represents the first attempt to encapsulate aqueous leaf extracts of Moringa oleifera within zein nanoparticles, developed and optimized using a Quality by Design methodology. Subsequently, an optimized topical gel formulation incorporating these nanoparticles was prepared and further assessed for its physicochemical properties, including pH, spreadability, extrudability, and storage stability. In vivo wound healing evaluations conducted on animal models demonstrated a significantly enhanced therapeutic efficacy (p < 0.05) of the Moringa-oleifera-extract-loaded zein nanoparticle gel compared to controls and gels containing the aqueous extract alone. According to the findings, zein nanoparticles can be utilized as effective carriers for herbal extracts, opening up new avenues for advanced therapeutic applications in herbal nanomedicine and topical wound care management [109]. Wound infection and impaired healing in diabetic patients remain significant challenges in clinical trauma management. Hence, developing advanced wound dressings tailored for diabetic wounds is crucial. In one study, an electrospun zein-based dressing membrane incorporating biological tea carbon dots (TCDs) and calcium peroxide (CaO₂) was designed to enhance diabetic wound repair, combining advantages such as biodegradability and an excellent biocompatibility. CaO₂, characterized by a microspherical structure, interacts with moisture to gradually release hydrogen peroxide and calcium ions, facilitating antimicrobial activity and tissue regeneration. Additionally, TCDs, owing to their nanoscale size, were integrated into the membrane to further enhance its antibacterial properties and wound-healing efficacy. To prepare the composite dressing, TCDs/CaO₂ were blended with ethyl cellulose-modified zein (ZE) solution and subsequently processed via electrospinning. This advanced membrane presented an improved therapeutic potential for diabetic wound management by combining sustained antimicrobial effects, biocompatibility, and accelerated tissue healing. Overall, these findings highlight the promising role of TCDs- and CaO₂-incorporated zein membranes as innovative dressings for effectively managing diabetic wound infections [110].

5.2.3. Other Nanoformulations Loaded with Phytochemicals and Extracts

Skin injuries and resulting wounds pose significant clinical challenges, prompting the continuous exploration of advanced therapeutic approaches to promote tissue regeneration. Among promising solutions, tissue engineering, particularly using polymeric scaffolds such as hydrogels, has gained considerable attention. CS and ALG are frequently utilized in hydrogel preparation for wound healing applications given their favorable biocompatibility, biodegradability, and supportive properties. Incorporating natural bioactive compounds, including essential oils and nettle (Urtica dioica) extracts, into these hydrogel scaffolds can significantly enhance wound repair processes. Employing nanocarriers such as nanoemulsions to encapsulate nettle extract and essential oils further improves their stability and bioavailability within the hydrogel matrix, thereby promoting more effective wound healing outcomes. In one study, nanoemulsions loaded with nettle extract and oil were successfully integrated into chitosan–alginate hydrogels, generating promising nanocomposite dressings. The developed nanocomposites demonstrated potent antibacterial activity, minimal cytotoxic effects, enhanced cell adhesion, a superior water absorption capacity, and an excellent hemocompatibility, highlighting their substantial potential as advanced dressing materials for effective wound healing [111]. Perovskia abrotanoides (P.a) karel is a medicinal plant known traditionally for its antimicrobial, anti-inflammatory, and antioxidant effects in wound treatment. Incorporating nanoemulsions (NEs) into chitosan gels has been demonstrated to enhance drug bioavailability, stability, skin penetration, and wound healing efficacy. One study evaluated the wound healing potential of a P.a essential oil nanoemulsion embedded in chitosan gel on full-thickness circular skin wounds in Wistar rats. The nanoemulsion was prepared using essential oil extracted from the flowering branches of Perovskia abrotanoides through ultrasonic emulsification and subsequently integrated into a 2% chitosan hydrogel, forming a P.a-NE-loaded chitosan gel. The optimized formulation was characterized by its particle size, stability, viscosity, and antimicrobial activity. Its in vivo wound healing effectiveness was assessed on days 3, 7, 14, and 21 post-application in Wistar rats. Histopathological analyses, including hematoxylin–eosin (HE) and Masson’s trichrome staining, were performed to evaluate tissue regeneration and collagen deposition within the wound area. The optimized P.a NE formulation demonstrated an average particle size of 13 ± 0.5 nm, a zeta potential of 2.9 ± 0.95 mV, and quasi-spherical morphology confirmed by transmission electron microscopy (TEM), exhibiting promising characteristics for clinical wound healing applications [112]. Lupeol, a pentacyclic triterpene, exhibits notable wound healing properties; nonetheless, its low water solubility limits its clinical use. To address this challenge, lupeol was encapsulated in silver-modified chitosan nanoparticles and subsequently incorporated into a thermosensitive, self-assembling sericin hydrogel. The results demonstrated that the lupeol encapsulation into the nanoparticles reached 62.1%, while exhibiting potent antibacterial properites against both Gram-positive and Gram-negative pathogens, alongside minimal hemolytic activity (<5%). The application of the CS-Ag-L-NPs sericin hydrogel to infected wounds markedly inhibited bacterial growth, accelerated re-epithelialization, mitigated inflammation, and improved collagen deposition, collectively enhancing overall wound healing outcomes. These findings suggest that the CS-Ag-L-NPs-loaded sericin hydrogel possesses substantial therapeutic potential for simultaneously enhanced wound repair and the effective control of microbial infections in wound management scenarios [113]. Table 2 shows various applications of phytochemical-loaded nanocarriers.

Table 2. Applications of the phytochemical-loaded nanocarriers.

Type of Nanocarriers	Materials	Phytochemical/Plant/Extract	Animal Models	Ref.
Nanoparticles	Aptamer functionalized mesoporous silica-coated UCNPs	Curcumin (Cur)	Yes	[103]
Nanoparticles	Hydrogel with zinc oxide	Gliricidia sepium	Yes	[104]
Nanoparticles	Chitosan-nano zinc oxide	Sericin	Yes	[105]
Nanoparticles	Bioreduced silver nanoparticles	Juglans regia L. pellicle extract	Yes	[106]
Nanoparticles/scaffolds	Silver nanoparticles (AgNPs) in chitosan/alginic acid scaffolds	Acer tegmentosum extract	Yes	[107]
Nanoparticles	Hordein/chitosan nanoparticles	Quercetin	Yes	[108]
Nanoparticles	Zein nanoparticles	Moringa oleifera	Yes	[109]
Carbon quantum dots	Zein-based electrospun membrane	Thea sinensis	N/A	[110]
Nanocomposite	Chitosan and alginate hydrogel with nanoemulsions	Urtica dioica	N/A	[111]
Nanogels	Chitosan based nanogels	Perovskia abrotanoides	Yes	[112]
Nanoparticles	Silver-modified chitosan nanoparticles	Lupeol	Yes	[113]

Table 2. Applications of the phytochemical-loaded nanocarriers.

Type of Nanocarriers	Materials	Phytochemical/Plant/Extract	Animal Models	Ref.
Nanoparticles	Aptamer functionalized mesoporous silica-coated UCNPs	Curcumin (Cur)	Yes	[103]
Nanoparticles	Hydrogel with zinc oxide	Gliricidia sepium	Yes	[104]
Nanoparticles	Chitosan-nano zinc oxide	Sericin	Yes	[105]
Nanoparticles	Bioreduced silver nanoparticles	Juglans regia L. pellicle extract	Yes	[106]
Nanoparticles/scaffolds	Silver nanoparticles (AgNPs) in chitosan/alginic acid scaffolds	Acer tegmentosum extract	Yes	[107]
Nanoparticles	Hordein/chitosan nanoparticles	Quercetin	Yes	[108]
Nanoparticles	Zein nanoparticles	Moringa oleifera	Yes	[109]
Carbon quantum dots	Zein-based electrospun membrane	Thea sinensis	N/A	[110]
Nanocomposite	Chitosan and alginate hydrogel with nanoemulsions	Urtica dioica	N/A	[111]
Nanogels	Chitosan based nanogels	Perovskia abrotanoides	Yes	[112]
Nanoparticles	Silver-modified chitosan nanoparticles	Lupeol	Yes	[113]

6. Conclusions and Future Perspectives

Currently, the proposed incorporation of natural herbs, plants, and extracts as wound dressing active molecules might be applied in clinical practice due to antibiotic resistance. In fact, many researchers propose the fabrication of innovative wound dressings based on traditional and commercially available products combined with the most effective phytochemicals exhibiting wound healing promotion and antimicrobial potency. Nonetheless, there are many limitations to the use of phytochemicals extracts, since the minimum efficient concentration dose can depend on many factors and can differ from plant to plant. However, nanotechnology-based systems can solve many problems; indeed, phytochemical-loaded nanosystems provide synergistic effects and can control wound infection and promote wound healing by combining the advantages of both phytochemicals and nanosystems. Nanosystems can be utilized to improve antimicrobial efficacy by stabilizing phytochemicals and enhancing bioavailability and solubility while delivering phytochemicals targeted into the wound site, thus accelerating wound healing. The use of phytochemical-loaded nanosystems to combat wound infections might be advantageous, but comes with various challenges, including scalability, regulatory approval, and toxicity risk factors.

Future studies should focus on the optimization of nanosystem formulations, as well as exploring new biocompatible nanomaterials, since, most often, PCL, PVA, CS, SA, and PLGA are used. Moreover, the scientific community should integrate more research into preclinical and clinical trials to justify the safety and efficiency of these systems. Throughout the literature, polymeric and inorganic nanoparticles, i.e., silver nanoparticles, are the most studied; the use of stimuli-responsive nanocarriers can further revolutionize the field, especially those of pH-responsive nanocarriers, since acute wounds reportedly present a pH around 7.44, while chronic wounds’ pH ranges from 7.42 to 8.9. Lipid nanoparticles can provide the improved penetration or permeation of phytochemical molecules into wounds, since they have been investigated extensively to deliver synthetic drugs to wound sites, enhancing wound repair. What the future holds for innovation in the wound healing field is unknown; nonetheless, AI driven design strategies can further revolutionize the wound dressing field. From the authors’ perspective, phytochemical-based nanotherapeutics can influence the wound care field and possibly offer sustainable and alternative solutions to conventional therapeutic options.