Introduction

The skin is an important organ that covers the human body and interacts directly with the outside world. It plays a key role in immunity, feeling, and protection.1,2 In recent years, the prevalence of chronic wounds has sharply increased, primarily due to the growing population of individuals with diabetes and obesity, in addition to external physical damage.3,4 Under normal conditions, wound healing is a complex, dynamic process supported by numerous cellular events, tightly coordinated to repair damaged tissues effectively.5 However, in certain situations such as diabetes, wound infection, inflammation, and vascular or neural dysfunction, the normal wound healing process becomes disrupted, leading to the development of chronic wounds.6,7 In the United States, chronic wounds affect approximately 10.5 million Medicare beneficiaries (an increase of 2.3 million since 2014), with annual treatment costs exceeding $25 billion.8,9 Despite advancements, promoting rapid and high-quality skin wound healing remains a significant challenge.

In recent years, silica nanoparticles (SNPs) and their multifunctional carriers have gained considerable attention due to their significant advantages in drug delivery.10–12 These advantages include their hydrophilic surface, diverse surface functionalization options, tunable shapes, and sizes, biocompatibility, ease of large-scale synthesis, and low production costs,10,13–15 making them highly promising therapeutic carriers. Among these, mesoporous silica nanoparticles (MSNs), with pore sizes ranging from 2 to 50 nanometers, have been extensively studied. MSNs have been applied in targeted drug delivery and tissue engineering,11,16 and their surfaces can be modified with stimuli-responsive molecules and various therapeutic macromolecules, enabling on-demand and localized controlled drug release.17 Additionally, capping strategies endow MSNs with intelligent drug delivery properties, allowing them to respond to various stimuli (eg, PH changes, photothermal, and photodynamic effects) and release therapeutic cargo for targeted applications.18 The development of silica-based nanosystems has shown significant potential in biomedicine, demonstrating their utility in clinical practice19–23 (Figure 1).

Figure 1 Applications of polymer-coated MSNs in various therapeutic fields, including photodynamic therapy (PDT), photothermal therapy (PTT), chemotherapy, RNA delivery, wound healing, tissue engineering, food packaging, and the treatment of neurodegenerative diseases. Reprinted from Nair A, Chandrashekhar H R, Day CM, et al. Polymeric functionalization of mesoporous silica nanoparticles: biomedical insights. Int J Pharm. 2024;660:124314. Creative Commons.19

Over the past few decades, advancements in nanotechnology have led to the emergence of various nanomaterials and nanomaterial-based drug delivery systems, which have been applied to wound repair and regeneration.24 The quantum size and surface effects of different nanomaterials impart unique physicochemical properties and functionalities, enabling them to carry and release bioactive drugs in controlled and sustained manners.25 These functionalized nanoparticles promote wound healing by modulating the microenvironment through antibacterial, anti-inflammatory, antioxidant, and pro-angiogenic properties.26–31 This review discusses different types of SNPs and their surface engineering, elucidating their mechanisms and potential roles in improving wound healing, while also exploring their biocompatibility and safety profiles.

Wound Classification and Pathophysiology of Injury Repair

Skin wounds are defined as disruptions or damage to the structure and function of the skin caused by various factors, including trauma, burns, and physiological or medical conditions.32,33 In such cases, the anatomical structure of the skin is compromised, leading to a loss of its physiological functions. Based on the healing timeline, wounds are generally classified into two categories: acute wounds and chronic wounds. Acute wounds are often caused by mechanical injury or exposure to extreme temperatures, radiation, electrical shocks, or corrosive chemicals.34 With proper wound management, acute wounds restore skin integrity within weeks or a month through the normal and orderly stages of tissue repair.35,36 Chronic wounds, however, are often complications of specific conditions such as diabetes, vascular diseases, or pressure ulcers, although wound-specific factors like infection, inflammation, and radiation also contribute.37 Systemic factors, including malnutrition, immunosuppression, aging, and other complications, can further delay wound healing.38,39 Wounds can also be classified based on their depth: superficial wounds (involving only partial epidermal loss), partial-thickness wounds (affecting the epidermis and deeper dermis), and full-thickness wounds (damaging subcutaneous fat and deeper tissues).40

Following injury, damaged skin initiates a complex repair process involving the interplay of various cell types, cytokines, and biological mediators. Under normal conditions, this process progresses through distinct stages, including hemostasis, inflammation, proliferation, and remodeling (Figure 2).33,41–43

Figure 2 Damaged skin initiates a complex repair process involving the interaction of multiple cell types, cytokines, and biological mediators. Under normal conditions, this process undergoes a series of stages, including hemostasis, inflammation, proliferation, and remodeling. Adapted from from Cioce A, Cavani A, Cattani C, Scopelliti F. Role of the Skin Immune System in Wound Healing. Cells. 2024; 13(7):624. Creative Commons.44

Hemostasis

Immediately after injury, the body triggers hemostatic responses to minimize blood loss. Local blood vessels constrict via smooth muscle contraction to limit blood flow, and both intrinsic and extrinsic coagulation pathways are activated.45,46 The fibrin clot formed by platelets and coagulation factors not only prevents bleeding but also provides a temporary scaffold for cell adhesion and migration.47–49

Inflammation

The inflammatory phase typically occurs from day 2 to day 5 post-injury. During this phase, platelets activated by thrombin release various growth factors, including epidermal growth factor (EGF), insulin-like growth factor-1 (IGF-1), platelet-derived growth factor (PDGF), fibroblast growth factor (FGF), and transforming growth factors (TGF-α and TGF-β).50,51 These factors serve as biological signals that attract neutrophils, monocytes, leukocytes, and macrophages to the wound site, mediating inflammation, protecting the skin from infection, and secreting additional growth factors to accelerate healing.40,52,53

Proliferation

From 3 days to 2 weeks post-injury, the wound enters the proliferative phase, characterized by cell proliferation and migration.40 Angiogenesis and capillary formation occur under the influence of pro-angiogenic factors such as PDGF released by platelets and inflammatory cells.54 Simultaneously, fibroblast migration is stimulated by PDGF and FGF, resulting in granulation tissue formation.55,56 Fibroblasts accumulate and proliferate, producing a new extracellular matrix (ECM) composed of collagen, proteoglycans, and elastin. Some fibroblasts differentiate into myofibroblasts, contributing to wound contraction.57 Additionally, activated keratinocytes at the wound edges migrate to the injured area, completing re-epithelialization.58

Remodeling

The remodeling phase involves structural reorganization and cellular reduction. Type III collagen in the granulation tissue is gradually replaced by type I collagen, the primary matrix component of the dermis. The rearrangement, cross-linking, and alignment of collagen fibers involve the dynamic synthesis of collagen and matrix metalloproteinases (MMPs), leading to ECM strengthening and contraction, and ultimately the formation of mature scar tissue. This phase typically lasts from 3 weeks to 2 years.59,60 Wound repair is a highly organized and complex pathological process. Disruptions at any stage can lead to wound pathologies, such as hypertrophic scars, keloids, or chronic wounds.61,62

If the normal healing process is disrupted, wounds may become chronic. Chronic wounds fail to heal in a timely and orderly manner. Clinically, diabetic foot ulcers (DFUs), pressure ulcers (PUs), and venous leg ulcers (VLUs) are common types of chronic wounds.37,39,63 Despite varying etiologies, these wounds share common characteristics, including excessive exudate, infection, tissue necrosis, insufficient re-epithelialization, reduced angiogenesis, and elevated levels of reactive oxygen species (ROS).64,65 Diabetes and hyperglycemia also contribute to peripheral neuropathy and peripheral vascular disease, significantly increasing the risk of DFUs and VLUs.66,67 Vascular damage leads to hypoxia, promoting the formation of avascular, non-viable tissue that creates an environment conducive to bacterial growth and biofilm formation. Biofilms exacerbate inflammation, hinder ECM deposition, and impair tissue repair.68 Unlike acute wounds, chronic wounds are influenced by multifactorial elements, including dysfunction of inflammatory cells; limited bioavailability of growth factors and cytokines; overexpression of proteases, persistent infection, reduced angiogenesis, and inadequate nutrient supply.53,69 These factors often interrupt the wound healing process, leaving it stalled in the inflammatory phase.

Diabetes significantly impacts all stages of wound repair, creating a pro-inflammatory environment characterized by elevated levels of pro-inflammatory cytokines such as TNF-α and reduced concentrations of healing-promoting mediators like IL-10 and TGF-β. This imbalance can lead to tissue necrosis and chronic wound formation.70 Additionally, the wound microenvironment after infection becomes pro-inflammatory, with prolonged presence of myeloid cells (eg, macrophages and neutrophils) and reduced levels of skin dendritic cells (DCs), Langerhans cells (LCs), and eosinophils, perpetuating the inflammatory state.64,71,72

Systemic or localized pathological factors often impair immune cells’ ability to eliminate pathogens, creating a vicious cycle that exacerbates the hostile wound microenvironment.73 Moreover, failure in signal transduction, weakened keratinocyte migration, and proliferation, and delayed re-epithelialization further contribute to chronic wound progression.71,74 Excessive ECM degradation, partly induced by the imbalance of MMPs and their inhibitors, hinders proper ECM deposition.75,76 In wounds with neuropathy, reduced neuropeptides and neurotrophic factors also impede critical healing mechanisms.76

Classification and Structural Characteristics of SNPs

The main synthesis methods of silicon-based nanomaterials include chemical vapor deposition (CVD), sol-gel method, solvothermal method, hydrothermal method, reverse microemulsion method, and self-assembly method.77–79 Due to their versatility in synthesis, size and shape regulation, surface functionalization, and biocompatibility, various types of silica nanoparticles (SNPs) have been developed for biomedical applications,77–80 including non-porous, mesoporous, hollow, core-shell, yolk-shell, and Janus architectures.81 Typically, SNPs are classified into two classic types—non-porous and mesoporous—based on their porosity (Figure 3). The term “mesoporous” generally refers to materials with pore sizes ranging from 2 to 100 nm.82 Non-porous SNPs lack special surface structures, while mesoporous silica nanoparticles (MSNs) feature tunable mesopores. The most notable difference between the two is the orderly, porous structure of MSNs.83 Characterization analysis shows that both types exhibit an amorphous, near-spherical morphology.

Figure 3 Silica MSNs-based nanocomposites developed in the biomedical field. Various nanostructured MSN-based nanocomposites. Depending on the assembly process, the functional nanostructures can be introduced as the shell (Type (I) or core (Type IV), loaded in the pore channels (Type II) or surface (Type III), or form Janus-type hierarchical structures (Type V). Reprinted from Xu B, Li S, Shi R, et al. Multifunctional mesoporous silica nanoparticles for biomedical applications. Signal Transduct Target Ther. 2023;8(1):435. Creative Commons.16

Amorphous SNPs not only provide drug-loading capabilities and enable precise regulation of pharmacokinetics through porous channels but also possess two critical functional surfaces: cylindrical pore surfaces and external particle surfaces. Both surfaces can be functionalized according to specific requirements. On the one hand, pore surfaces can be specifically functionalized to precisely control drug release rates and mechanisms; on the other hand, external particle surfaces can bind to targeting ligands to achieve specific drug delivery.84 According to assembly strategies, specific nanostructured composites can be obtained, and MSNs are categorized into five types16 (Figure 3):

Type I: Core-shell structures where MSNs act as the core, and functional components serve as the shell. Functional nanocoatings of specific sizes can be easily achieved by manipulating MSNs as hard templates. Type II: Small functional components are directly loaded into MSN pores. Common functional components, such as carbon quantum dots and black phosphorus quantum dots, are often encapsulated in this form. In such structures, MSNs enable the slow and controlled release of small functional components. Type III: Functional components are loaded onto MSN surfaces or pore peripheries through covalent bonds or electrostatic adsorption. This approach avoids masking the active sites of functional components, thereby ensuring catalytic stability. Type IV: Core-shell structures where MSNs act as the shell, and functional components serve as the core. This structure prevents the aggregation of exposed inorganic functional components, enhancing the stability of nanocomposites and reducing physiological toxicity. Type V: Janus-type architecture. Janus-type nanocomposites feature biphasic geometric shapes with distinct compositions or anisotropic structures. Unlike the Type I–IV nanocomposites, the physicochemical properties of individual components in Janus structures remain largely unaffected.

Using these unique structures, researchers have developed numerous silicon-based hybrid nanomaterials with distinctive properties through surface functionalization, such as silicon-drug polymers, silicon-nucleic acid hybrids, silicon-protein hybrids, and silicon-magnetic composites. Additionally, silica can hybridize with peptides, amino acids, gold nanomaterials, and quantum dots to meet the demands of complex biomedical applications.85,86

In recent years, experts have continually proposed new insights into the design principles of silica nanostructures,87 such as engineering pore geometry, surface topology, and asymmetry to enhance the efficiency of drug, gene, and protein delivery.87,88 Innovations include altering surface roughness to improve cellular uptake and adhesion, as well as hollow MSNs (HMSNs) with mesoporous shells and hollow interiors. Another class of innovative mesoporous silica materials has been designed to overcome the limitations of traditional MSNs in delivering large-volume drugs like proteins by exhibiting advanced mass diffusion properties and high storage capacities.88–90 Additionally, novel SNPs have been designed as biological modulators to regulate intracellular microenvironments and cell signaling, such as oxidative stress and glutathione levels, thereby enhancing therapeutic anticancer effects and mRNA transfection in specific cell lines91 (Figure 4). Thus, silicon-based nanomaterials are becoming increasingly diverse in terms of morphology and functionality, finding widespread applications in biomedical fields, including targeted drug delivery, tissue engineering, biosensing, bioimaging, and more.92

Figure 4 Schematic illustration of the composition and architecture of engineered silica-based nanoparticles with diverse appealing properties as nanocarriers and biomodulators for biomedical applications. Reprinted from Fu JY, Gu Z, Liu Y, et al. Bottom-up self-assembly of heterotrimeric nanoparticles and their secondary Janus generations. Chem Sci. 2019;10(44):10388–10394. Creative Commons.91

Potential Regulatory Mechanisms of Silicon-Based Nanomaterials in Wound Healing

Silicon-based nanoparticles (SNPs) have shown immense potential in tissue regeneration, particularly in wound healing. Silicon-based nanostructured composites exhibit promising roles, either individually or synergistically, in promoting wound healing through antibacterial/anti-inflammatory effects, antioxidation, and tissue regeneration.93,94 Below, we elucidate their potential regulatory mechanisms with illustrative examples.

Antibacterial Effects

After skin injury, bacteria easily migrate from the surface to non-resident areas, leading to wound infection and significantly disrupting the healing process.37 Wound exudates, as a hallmark of chronic wounds, contain corrosive components that exacerbate extracellular matrix (ECM) degradation. Matrix metalloproteinases (particularly MMP-9) have been identified as key destructive factors, and the increase in bacterial load is closely associated with elevated MMP-9 levels.95 Furthermore, biofilm formation provides bacteria with protection, enhances their proliferation, and increases their resistance to antibacterial treatments, which is a major cause of chronic wound infections.96 With the growing prevalence of bacterial antibiotic resistance, effectively treating chronic infections and promoting wound healing has become increasingly challenging. Silicon-based nanocomposites have garnered significant attention in wound healing due to their excellent antibacterial properties. Their antibacterial and anti-infection effects are primarily attributed to two mechanisms: serving as physical barriers and releasing antibacterial active substances.97,98

Figure 5 (I) TEM images (a and b), with the nano-Ag particle size distribution shown in the inset of (a), dark field image (c), corresponding elemental mapping for silicon (d), oxygen (e), silver (f), Si-Ag-O merged image (g), nitrogen sorption isotherm (h), and the inset showing pore size distribution for SiNPs-Ag. (II) SEM images of E. coli (a–d) and S. epidermidis (e–h) after treatment with vancomycin (a, e), SiNPs-Van (b, f), SiNPs-Ag (c, g), and SiNPs-Ag-Van (d, h), along with a schematic illustration of antibacterial activity (i). Reprinted from Ni C, Zhong Y, Wu W, et al. Co-Delivery of Nano-Silver and Vancomycin via Silica Nanopollens for Enhanced Antibacterial Functions. Antibiotics. 2022;11(5):685. Creative Commons.98 (III) Schematic description of the preparation of Ag-Bi@SiO2 NPs and their synergistic antibacterial effects. Reprinted from Cao CY, Ge W, Yin J, et al. Mesoporous Silica Supported Silver-Bismuth Nanoparticles as Photothermal Agents for Skin Infection Synergistic Antibacterial Therapy. Small. 2020;16(24). © 2020 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.99

Note: The original figure contains a spelling error “quantaty”, which is retained as published.

Silicon-based nanosystems are commonly used as multifunctional delivery platforms to load and release antibacterial active substances to inhibit pathogen growth. For example, Ni et al successfully loaded vancomycin and nanosilver onto pollen-shaped silica nanoparticles. The unique spiked morphology of the silica carrier enhanced nanoparticle adhesion to bacterial surfaces, thereby promoting local drug release for bacterial eradication. This dual delivery of vancomycin and nanosilver demonstrated enhanced bactericidal activity98 (Figure 5I and II). Additionally, Cao et al constructed mesoporous silica nanoparticles loaded with silver-bismuth nanoparticles (Ag-Bi@SiO2NP). The high-temperature effect of bismuth nanoparticles accelerated the release of Ag ions, exhibiting excellent antibacterial performance against methicillin-resistant Staphylococcus aureus (MRSA)99 (Figure 5III). Rasool et al developed functionalized silica-ceria nanocomposites (FSC), which combined mesoporous silica nanoparticles with ceria’s inherent antibacterial activity, effectively inhibiting biofilm formation.100

Figure 6 (I) Silicon-based Ag dendritic nanoforests for light-assisted bacterial inhibition. Reprinted from Li Y, Xu T, Tu Z, et al. Bioactive antibacterial silica-based nanocomposites hydrogel scaffolds with high angiogenesis for promoting diabetic wound healing and skin repair. Theranostics. 2020;10(11):4929–4943. Creative Commons.22 (II) Top- and side-view SEM images of Ag-DNFs/Si synthesized at various times. (III) Schematic of plasmonic-assisted bacterial inhibition. Reprinted from Huang HJ, Chang H-W, Lin Y-W, et al. Silicon-Based Ag Dendritic Nanoforests for Light-Assisted Bacterial Inhibition. Nanomaterials. 2020;10(11):2244. Creative Commons.101

The smart-responsive properties of silicon-based nanomaterials further enhance their antibacterial efficacy. For instance, Li et al developed a silicon-based nanocomposite hydrogel scaffold with biomimetic elastic mechanics, self-healing behavior, and broad-spectrum antibacterial activity. This scaffold significantly enhanced the vitality and angiogenic capability of endothelial progenitor cells (EPCs) in vitro and promoted collagen deposition and vascular network reconstruction by enhancing HIF-1α/VEGF expression in vivo, thereby accelerating full-thickness wound healing22 (Figure 6I). Moreover, specific nanostructure designs of silicon-based materials, such as sharp nanoblades, microspheres, and nanoflower-like structures, further improve their antibacterial effects. Huang et al synthesized silver dendritic nanoforests (Ag-DNFs/Si) on silicon substrates. The sharp nanoblade structures exhibited superior antibacterial efficiency, showing significant bactericidal effects against Escherichia coli and Staphylococcus aureus101 (Figure 6II and III).

Silicon-based nanoparticles can also be specifically designed to meet diverse needs. Khan et al prepared silica microspheres loaded with nitrofurazone (NFZ) and lidocaine (LD). The successful incorporation of drugs into the microspheres avoided drug-drug interactions and effectively addressed pathological skin infections. In-vitro and in-vivo experiments demonstrated good antibacterial activity and biocompatibility.102 Hashemikia et al prepared hybrid nanofibers of chitosan/polyethylene oxide/silica, incorporating ciprofloxacin into the electrospun mixture. The nanofibers absorbed moisture during degradation and gradually released ciprofloxacin, exhibiting excellent antibacterial activity against E. coli and S. aureus.103 Gwon et al synthesized antibacterial silicon-based nickel nanoflowers (Si@Ni) using microfluidics and photopolymerization techniques and encapsulated them in methacryloyl gelatin (GelMA) to construct uniform microscale hydrogel spheres (Si@Ni-GelMA). Due to nickel’s antibacterial effects against Pseudomonas aeruginosa, Klebsiella pneumoniae, and MRSA, the injectable Si@Ni-GelMA demonstrated superior antibacterial activity with negligible cytotoxicity.104 By acting as physical barriers, releasing antibacterial active substances, and leveraging smart-responsive properties, silicon-based nanomaterials not only address antibiotic resistance but also significantly accelerate wound healing. Additionally, their customizable designs for various drug metabolism needs make them ideal materials for wound repair applications (Table 1).

Table 1 Application of Silicon-Based Materials in Antibacterial Therapy

Inflammation Regulation

Inflammation is a critical stage of wound healing; however, excessive or persistent inflammation, often accompanied by microbial recruitment and biofilm formation, leads to chronic wound formation. Regulating inflammatory responses to maintain immune balance is one of the key strategies for promoting wound healing.105,106 In recent years, silicon-based nanomaterials have demonstrated significant advantages in regulating chronic wound inflammation due to their unique structural properties and functionalization potential as drug carriers for inflammatory modulators (Table 2).

Table 2 Application of Silicon-Based Materials in Anti-Inflammatory Therapy

Single silicon-based monomers containing carboxylated antibiotics, specifically norfloxacin, and anti-inflammatory agents, such as ibuprofen, were developed. Liu et al covalently linked silicon nanoparticles (SNPs) derived from these single silicon-based monomers with the anti-inflammatory and antibacterial drugs through amide bonds. This process resulted in the synthesis of bifunctional SNPs that exhibit both inflammation-regulating and antibacterial activities.107 Additionally, quercetin, a plant-derived anti-inflammatory drug, was loaded onto calcium carbonate/silica nanocomposites to exert anti-inflammatory effects and improve wound healing rates.108 These silicon-based nanosystems function as drug carriers to modulate inflammatory responses, thereby optimizing the wound healing environment.

Moreover, macrophages play a crucial role in wound healing, with their polarization states determining the progression of inflammation and the efficiency of tissue repair. During the early inflammatory stage, M1 macrophages function to clear pathogens, but their overactivation can delay healing. In the later repair stage, M2 macrophages accelerate tissue regeneration by secreting anti-inflammatory factors (eg, IL-10) and pro-repair factors (eg, VEGF).111 Scholars have designed various silicon-based composites to effectively promote macrophage polarization from M1 to M2. For example, MSN-loaded hydrogels significantly inhibited pro-inflammatory M1 macrophages while promoting anti-inflammatory M2 macrophages, accelerating tendon healing and reducing inflammatory responses109 (Figure 7I). Liu et al fabricated magnesium-doped SiO2 bioactive glass composite membranes using electrospinning technology. The release of magnesium ions significantly suppressed the expression of the pro-inflammatory factors IL-6 and TNF-α while inhibiting M1 macrophage polarization, thereby enhancing anti-inflammatory effects110 (Figure 7II).

Figure 7 (I) (A) Preparation of CP@SiO2 composite by combining puerarin, chitosan, and SiO2 nanoparticles. (B) Structure of CP@SiO2 hydrogel showing uniform distribution of SiO2 within the network. (C) Application in Achilles tendon injury to achieve in situ repair. (D) Regulation of extracellular matrix (ECM) and cellular behaviors, including macrophage polarization and fibroblast activity. (E) Schematic mechanism showing CP@SiO2-mediated signaling pathways that regulate inflammation, fibrosis, proliferation, and apoptosis. Reprinted from Wan R, Luo Z, Nie X, et al. A Mesoporous Silica-Loaded Multi-Functional Hydrogel Enhanced Tendon Healing via Immunomodulatory and Pro-Regenerative Effects. Adv Healthc Mater. 2024;13(26):e2400968. © 2024 Wiley-VCH GmbH.109 (II) (A) Synthesis scheme of precursor solutions for electrospinning. (B) Synthesis and chemical structure of flexible inorganic SiO2/MgO nanofiber membranes. (C) Electrospun flexible SiO2/MgO nanofiber membranes inhibit S. aureus infection and promote the healing of infected wounds. Reprinted from Liu MY, Wang X, Cui J, et al. Electrospun flexible magnesium-doped silica bioactive glass nanofiber membranes with anti-inflammatory and pro-angiogenic effects for infected wounds. J Mat Chem B. 2023;11(2):359–376. © Royal Society of Chemistry 2023.110

Through the release of anti-inflammatory factors, inhibition of pro-inflammatory signals, regulation of macrophage polarization, or synergistic mechanisms, silicon-based nanomaterials demonstrate significant potential in inflammation regulation, making them promising candidates for research and applications in chronic wound healing.

Antioxidant Effects

Reactive oxygen species (ROS) play a dual role in the wound healing process. At physiological levels, ROS act as signaling molecules to regulate cell migration, angiogenesis, and immune responses. However, in chronic wounds or infected wounds, excessive ROS can induce oxidative stress, damage cellular structures and functions, and lead to the oxidative modification of proteins, lipids, and DNA, further exacerbating tissue inflammation and damage.112–114 This persistent oxidative stress inhibits the proliferation of fibroblasts and keratinocytes, thereby delaying wound healing.115 Thus, eliminating excessive ROS and providing sustained antioxidant protection are critical for accelerating wound repair.

Table 3 Application of Silicon-Based Materials in Combating Oxidative Stress

Figure 8 (I) Nanoparticles demonstrated multifunctional therapeutic effects by disrupting biofilms, eradicating E. coli, neutralizing reactive oxygen species (ROS), stimulating fibroblast growth, and enhancing angiogenesis. Additionally, they suppressed inflammatory cytokines while upregulating factors involved in cell proliferation and vascular formation, ultimately facilitating wound repair in experimental models. Reprinted from Shen Y, Jia T, Zeng J, et al. Broad-Spectrum Bactericidal Multifunctional Tiny Silicon-Based Nanoparticles Modified with Tannic Acid for Healing Infected Diabetic Wounds. ACS Appl Mater Interfaces. 2024;16(46):63241–63254. Copyright © 2024 American Chemical Society.117 (II) Res_GSH@SNP exerts antibacterial effects by binding to bacterial surface receptors, disrupting membrane potential, inducing ROS production, causing membrane damage, and leading to DNA degradation. Reprinted from Verma M, Nisha A, Bathla M, et al. Resveratrol-Encapsulated Glutathione-Modified Robust Mesoporous Silica Nanoparticles as an Antibacterial and Antibiofilm Coating Agent for Medical Devices. ACS Appl Mater Interfaces. 2023;15(50):58212–58229. Copyright © 2023 American Chemical Society.119

Silicon-based nanomaterials, owing to their unique structures and bioactivity, are widely applied in ROS scavenging (Table 3). On one hand, silicon-based nanomaterials can act as drug carriers with antioxidant effects. For instance, tannic acid-modified silicon nanoparticles (TA-SNPs) have demonstrated significant free radical scavenging potential in antioxidant experiments. Additionally, TA-SNPs exhibit efficient intracellular ROS scavenging ability117 (Figure 8I). On the other hand, silicon ions themselves possess antioxidant properties. For example, silicon ions at optimal concentrations enhance ROS metabolism and scavenging under oxidative stress conditions in C2C12 cells, protecting them from oxidative damage and promoting skeletal muscle cell regeneration.116 Furthermore, silicon ions released from amorphous silicon nitride surfaces can enhance superoxide dismutase (SOD1) activity and significantly promote collagen matrix formation by increasing antioxidant expression.120

Moreover, the functionalization of silicon-based nanomaterials can further enhance their antioxidant activity. Ashraf et al synthesized MnS2-SiO2 nano-heterojunction photocatalysts with varying MnS2 contents, demonstrating antioxidant activity through DPPH radical scavenging.118 Additionally, silicon-based nanocomposites with combined antioxidant and antibacterial properties have been reported to promote wound healing more effectively. For instance, functionalized silicon nanoparticles conjugated with antioxidants such as glutathione or vitamin C enhance their antioxidant effects, creating an optimal microenvironment for wound healing. Researchers have used glutathione (GSH) to modify biosilica nanoparticles, forming GSH@SNPs, which can target bacterial surfaces and biofilms. By loading resveratrol onto GSH@SNPs, they developed ResGSH@SNPs, which bind to bacterial surface receptors, disrupt membrane potential, induce excessive ROS production, cause membrane damage and DNA disruption, and ultimately exhibit antibacterial activity119 (Figure 8II).

The application of silicon-based materials in oxidative stress management for wound healing is progressing toward multifunctionality and intelligence. Enhancing material stability and achieving sustained release of antioxidant components through structural optimization remain key challenges to address.

Promoting Angiogenesis

Angiogenesis is an indispensable biological process in wound healing. In chronic wounds, insufficient local angiogenesis often leads to hypoxia and limited nutrient supply, thereby delaying tissue repair and regeneration. Thus, stimulating angiogenesis at the wound site is considered a crucial strategy for treating chronic wounds. Silicon-based composite nanomaterials, with their unique bioactivity and tunable physicochemical properties, exhibit significant potential in promoting angiogenesis and accelerating wound healing (Table 4).

Table 4 The Role of Silicon-Based Materials in Promoting Angiogenesis

Studies have shown that appropriate concentrations of silicon ions (Si4+) can significantly enhance angiogenesis by upregulating pro-angiogenic factors such as vascular endothelial growth factor (VEGF), CD31, and α-smooth muscle actin (α-SMA).121,122 Wang et al prepared short SiO2 nanofibers via electrospinning and blended them with varying proportions of tricalcium phosphate (TCP) to fabricate TCPx@SSF aerogel scaffolds. These scaffolds released Si4+, significantly upregulating VEGF and α-SMA expression, thereby promoting angiogenesis123 (Figure 9I). Li et al designed a dual-network silica-based nanocomposite hydrogel scaffold that, without the addition of any bioactive factors, significantly enhanced early angiogenesis and promoted diabetic wound healing.22

Figure 9 (I) Schematic representation of the interactive and dynamic healing mechanisms of TCPx@SSF dressings during wound repair. Reprinted from Wang XY, Yuan Z, Shafiq M, et al. Composite Aerogel Scaffolds Containing Flexible Silica Nanofiber and Tricalcium Phosphate Enable Skin Regeneration. ACS Appl Mater Interfaces. 2024;16(20):25843–25855. Copyright © 2024 American Chemical Society.123 (II) Mesoporous silica nanoparticles (MSNs) modified with polyethyleneimine (PEI) and functionalized with the endothelial-recognition pentapeptide YIGSR enable precise delivery of miR-146a inhibitors, significantly boosting angiogenesis. Reprinted from Wang Y, Wu J, Feng J, et al. From Bone Remodeling to Wound Healing: an miR-146a-5p-Loaded Nanocarrier Targets Endothelial Cells to Promote Angiogenesis. ACS Appl Mater Interfaces. 2024;16(26):32992–33004. Copyright © 2024 American Chemical Society.124

Furthermore, the functionalized design of silicon-based materials is particularly notable Functionalized silicon-based materials can carry pro-angiogenic factors (eg, VEGF, FGF) or nucleic acids (eg, miRNA) for precise release. Wang et al functionalized mesoporous silica nanoparticles (MSNs) with polyethyleneimine (PEI) and modified their surface with a pentapeptide (YIGSR) capable of recognizing endothelial cells. This system delivered miR-146a inhibitors with high precision, significantly enhancing angiogenesis124 (Figure 9II). Combining silicon nanoparticles with other biomaterials can further enhance their pro-angiogenic properties. For example, hollow silica nanoparticles (HSNs) loaded with RL-QN15 peptide and incorporated into a zinc alginate (ZA) hydrogel formed HSN@RL-QN15/ZA hydrogels. These hydrogels effectively regulated angiogenesis, significantly reduced inflammation, and accelerated epithelial regeneration and granulation tissue formation, thereby promoting rapid healing of chronic wounds.125

In summary, silicon-based nanomaterials demonstrate great potential in promoting angiogenesis and accelerating wound healing through silicon ion release, loading of pro-angiogenic factors, and optimizing material microstructures. Their multifunctional design not only improves therapeutic efficiency but also provides new strategies for the comprehensive treatment of chronic wounds.

Promoting Cell Adhesion, Migration, and Proliferation

The proliferation phase of wound healing is characterized by cell proliferation and migration. During this phase, angiogenic factors actively promote new blood vessel formation, which further supports the proliferation and migration of fibroblasts. These fibroblasts accumulate and act at the wound site, producing new extracellular matrix (ECM) that eventually forms granulation tissue.54,126 A subset of fibroblasts differentiates into myofibroblasts, playing a crucial role in wound contraction.57 Additionally, keratinocyte proliferation and migration are essential for epidermal regeneration.127,128

Cell adhesion is a prerequisite for proliferation and migration, directly impacting wound healing efficiency. Studies have shown that functionalized silicon-based nanomaterials significantly enhance cell adhesion. For example, Zhang et al investigated the effects of glycine-aspartic acid (RGD)-functionalized mesoporous silica nanoparticles (MSNs-RGD) on stem cell adhesion and differentiation. Results indicated that when the total RGD density increased from 1.06 to 5.32 nmol/cm², cell adhesion and spreading significantly improved, suggesting that MSNs-RGD could serve as drug carriers to promote cell adhesion and proliferation129 (Figure 10I). Furthermore, Motealleh et al incorporated bifunctional nanomaterials into glass and polydimethylsiloxane surfaces, creating a hybrid nanocomposite material. This material significantly enhanced cell adhesion and proliferation while inhibiting bacterial biofilm formation, demonstrating excellent antibacterial properties and biocompatibility.130

Figure 10 (I) Fabrication of mesoporous silica nanoparticle-based films with adjustable densities and clustering levels of arginine–glycine–aspartate peptides to investigate stem cell adhesion and differentiation. Reprinted from Zhang X, Karagöz Z, Swapnasrita S, et al. Development of Mesoporous Silica Nanoparticle-Based Films with Tunable Arginine–Glycine–Aspartate Peptide Global Density and Clustering Levels to Study Stem Cell Adhesion and Differentiation. ACS Appl Mater Interfaces. 2023;15(32):38171–38184. Creative Commons.129 (II) (A) Illustration of the preparation process for PCL/Gel-Pio nanofiber membranes. (B) Mechanistic depiction of the genipin-induced cross-linking reaction in the fiber membrane. (C) Mechanism by which the fiber membrane enhances diabetic wound healing. Reproduced from Gao ZJ, Wang Q, Yao Q, et al. Application of Electrospun Nanofiber Membrane in the Treatment of Diabetic Wounds. Pharmaceutics. 2022;14(1):6. Creative Commons.131 (III) A directional porous composite membrane (DS-PL) was developed using polylactic acid (PLLA) electrospun fibers incorporating mesoporous silica nanoparticles (DS) loaded with dimethyloxalylglycine (DMOG). The system facilitates controlled DMOG and silicon ion release, enhancing HUVEC proliferation, migration, and angiogenesis-related gene expression, which accelerates vascularization in diabetic wound environments. Reprinted from Acta Biomater. Volume 70. Ren XZ, Han Y, Wang J, et al. An aligned porous electrospun fibrous membrane with controlled drug delivery - An efficient strategy to accelerate diabetic wound healing with improved angiogenesis. 140–153, copyright 2018, with permission from Elsevier.132

In tissue engineering research, cell migration ability is a critical indicator of cell proliferation and its role in wound repair. Silicon-based nanomaterials have been shown to promote cell migration, thereby supporting wound healing. For instance, TA-SNP exhibited outstanding efficacy in treating full-thickness wounds in diabetic mice infected with E. coli. At a TA-SNP concentration of 100 μg/mL, the cell migration rate increased from 9.19% to 18.21%, further rising to 30.98% at a concentration of 500 μg/mL. This significant effect is attributed to the positive impact of silicon nanoparticles on cell proliferation, migration, and wound repair.117 Silicon-based materials also support cell proliferation through various pathways. Shie et al found that appropriate concentrations of Si ions significantly promoted the proliferation of osteoblast-like cells while inducing specific biological responses through bone-specific protein synthesis in MG63 cells. Cells maintained normal morphology and proliferated well under these conditions, further validating the excellent biocompatibility of silicon-based materials.133,134

The structure and micro-morphology of scaffolds are critical for cell adhesion, migration, and proliferation. Gao et al successfully developed silica-SFO-P scaffolds using extrusion-based 3D printing and validated their performance through direct cell biocompatibility tests. The porous structure of the scaffold significantly supported L929 cell adhesion and proliferation, with cells demonstrating robust growth on the scaffold surface and within its pores after three weeks of culture131 (Figure 10II). Ren et al fabricated a directional porous composite membrane (DS-PL), a polylactic acid (PLLA) directional electrospun fiber membrane containing mesoporous silica nanoparticles (DS). By loading the drug dimethyloxalylglycine (DMOG), controlled release of DMOG and Si ions was achieved. The combined directional porous structure and functional components synergistically promoted the proliferation, migration, and expression of angiogenesis-related genes in human umbilical vein endothelial cells (HUVECs), rapidly stimulating angiogenesis in diabetic wound beds, offering a novel therapeutic strategy for efficient diabetic wound healing132 (Figure 10III). In summary, silicon-based nanomaterials systematically enhance cell adhesion, migration, and proliferation by optimizing surface chemical properties, functional design, and regulating biological signals in the local microenvironment, thereby promoting wound healing (Table 5).

Table 5 The Role of Silicon-Based Materials in Promoting Cell Adhesion, Migration, and Proliferation

Promoting Extracellular Matrix Deposition

The extracellular matrix (ECM) is an indispensable structural and functional unit in wound healing, primarily produced and organized by myofibroblasts. ECM serves as both a structural scaffold for cells and a reservoir of cytokines and growth factors, interacting with surrounding cells to regulate critical behaviors during their life cycle, including migration, growth, proliferation, differentiation, and morphogenesis.135,136 Major ECM components include interstitial collagen and elastic fibers, non-collagenous proteins (eg, fibronectin and laminin families), glycosaminoglycans (GAGs), and proteoglycans (PGs). These molecules collectively provide mechanical support to cells while regulating cellular behavior. Silicon, as a component of certain GAGs and PGs, participates in GAG synthesis. By binding to polysaccharide matrices, silicon acts as a biological crosslinker, enhancing the structure and elasticity of connective tissues and further promoting ECM deposition.137

Figure 11 (I) Jiang et al designed an electrospun scaffold featuring uniformly distributed silicon-doped amorphous calcium phosphate nanoparticles (Si-ACP/PM, ~40 nm diameter). The scaffold released silicon ions gradually, enhancing collagen deposition and re-epithelialization in diabetic wound models. Reprinted from Jiang Y, Han Y, Wang J, et al. Space-Oriented Nanofibrous Scaffold with Silicon-Doped Amorphous Calcium Phosphate Nanocoating for Diabetic Wound Healing. ACS Appl Bio Mater. 2019;2(2):787–795. Copyright © 2019 American Chemical Society.138 (II) (A) TEM visualization of MSNs. (B) Photograph showing the UV cross-linked GelMA/HAMA. Hydrogel.flowing liquid (B1) before cross-linking and gradually changed into a solid phase after the UV curing (B2). (C) ¹H NMR analysis of Gel and GelMA. The distinctive double peaks (δ = 5.4 and 5.6 ppm), marked by the black arrows, were observed in GelMA. (D) ¹H NMR analysis of HA and HAMA. The distinctive double peaks (δ = 5.7 and 6.1 ppm), marked by the black arrows, were observed in HAMA. (E) FTIR spectra comparing Gel and GelMA. (F) SEM images of GelMA/HAMA hydrogels prepared with varying HAMA concentrations. Reprinted from Xue LY, Deng T, Guo R, et al. A Composite Hydrogel Containing Mesoporous Silica Nanoparticles Loaded With Extract for Improving Chronic Wound Healing. Front Bioeng Biotechnol. 2022;10:825339. Creative Commons.139

During the remodeling phase of wound healing, collagen deposition plays a pivotal role in enhancing tissue strength and supporting wound contraction. Studies have shown that silicon-based materials significantly promote collagen deposition, thereby accelerating wound repair. For example, Jiang et al designed an electrospun scaffold with uniformly distributed silicon-doped amorphous calcium phosphate nanoparticles (Si-ACP/PM) approximately 40 nm in size. This scaffold continuously released silicon ions, promoting collagen deposition and re-epithelialization in diabetic wound beds, effectively accelerating wound healing138 (Figure 11I). Through functionalization, silicon-based nanocomposites demonstrate multifunctionality in promoting ECM deposition and wound repair. For instance, Masson staining revealed that diabetic wounds treated with double-network silica-based nanocomposite hydrogel scaffolds exhibited excellent collagen deposition and tissue remodeling, along with effective vascular network repair.22 Additionally, Xue et al developed a hydrogel based on gelatin methacrylate (GelMA)/hyaluronic acid methacrylate (HAMA) and mesoporous silica nanoparticles (MSNs), with artemisia extract (AE) loaded for sustained release. This GelMA/HAMA/MSNs@AE hydrogel accelerated wound healing by promoting re-epithelialization and collagen deposition139 (Figure 11II). In summary, silicon-based materials offer significant advantages in promoting collagen deposition and improving chronic wound repair, providing innovative ideas for developing efficient wound repair materials (Table 6).

Table 6 The Role of Silicon-Based Materials in Extracellular Matrix Deposition

Multimechanism Synergy

The pathological causes of refractory wounds are often complex and diverse. Thus, leveraging the overlapping and synergistic effects of two or more functions of silicon-based nanomaterials—including antibacterial properties, antioxidation and anti-inflammation, angiogenesis promotion, cell proliferation and migration promotion, and tissue remodeling promotion—can significantly accelerate the wound healing process. For instance, Xi et al developed biodegradable bioactive elastic multifunctional PPCP nanofiber scaffolds. The optimized assembly and combination of the multifunctional elastomer polylactic acid/polysiloxane citrate/curcumin endowed PPCP scaffolds with inherent multifunctionality. PPCP significantly promoted normal and infection-induced wound healing through infection prevention, reduction of proinflammatory factors, upregulation of CD31 and VEGF growth factors, stimulation of collagen deposition, and promotion of dermal and skin appendage formation.