Nanotechnology for the Treatment of Radiation Dermatitis: Advances and Translational Perspectives

Abstract

Radiation dermatitis is the most common complication of radiotherapy, but conventional treatments only alleviate some symptoms, with limited efficacy and safety, thus necessitating the exploration of novel therapeutic strategies. This review synthesizes current understanding of radiation dermatitis pathogenesis, and highlights recent advances enabled by nanomaterial-based strategies. We categorize nanomaterials according to their mechanisms of action and pathological stage-specific application in radiation dermatitis. Fullerene alcohol, a representative direct antioxidant material—has demonstrated preliminary clinical efficacy; immune microenvironment-modulating materials exert therapeutic effects on chronic inflammation and fibrosis via synergistic, multi-pathway regulation; and composite biomaterials enable coordinated, multi-targeted repair. We further identify key translational barriers impeding clinical translation: biological safety, scalable manufacturing, regulatory uncertainty, and tumor safety risks. Future efforts should prioritize collaborative safety assessment, scalable manufacturing, and stage-tailored clinical trials to accelerate the clinical adoption of nanomaterials.

Introduction

Radiation dermatitis is a common complication for cancer patients after radiotherapy, usually occurring within 1 to 4 weeks after treatment.^1,2 As many as 95% of patients with malignant tumors, especially those with head and neck cancers and breast cancers, will experience moderate to severe skin reactions.^3,4 Radiation dermatitis manifests as widespread erythema, severe pain, skin ulceration, mottled desquamation, marked edema, intractable pruritus, and a burning sensation.^5,6 Severe radiation dermatitis may interrupt radiotherapy, compromising tumor control and imposing substantial physical, psychological, and financial burdens on patients.⁷

Radiation dermatitis arises from four interrelated processes—oxidative stress, immune microenvironment imbalance, microvascular damage, and fibrosis—that progress from acute inflammation to chronic tissue remodeling.^8,9 Therefore, an effective treatment strategy needs to take into account both the management of acute injury and the inhibition of the long-term inflammatory and fibrotic processes.^10,11 However, traditional treatments such as glucocorticoids, growth factors, hyperbaric oxygen therapy and laser therapy have limited efficacy due to their poor targeting ability, single mechanism of action and insufficient anti-fibrotic effects.^12,13 Therefore, nanomaterials are widely used for its efficient cellular uptake,¹⁴ chemical stability, and multi-targeted delivery.^15,16 Through engineering design, it can achieve multiple functions such as eliminating reactive oxygen species (ROS),¹⁷ regulating the immune microenvironment,¹⁸ promoting angiogenesis,¹⁹ and resisting fibrosis.^20,21 Furthermore, it can simultaneously enhance the efficacy of tumor radiotherapy and the treatment of radiation-induced dermatitis.²²

This review systematically examines the pathogenesis of radiation dermatitis, limitations of conventional therapies, and recent advances in nanomaterial-based interventions.^23,24 We classify nanomaterials by their mechanisms and targeted distinct pathological stages of radiation dermatitis—from acute oxidative damage to chronic fibrosis^25,26 (Table 1). We also analyze clinical adoption challenges—biological safety, manufacturing complexity, and regulatory hurdles—to guide the development of safe, efficient, multi-targeted nanomaterials for radiotherapy sensitization (Figure 1).

Table 1.

Application of Nanotechnology Materials in Radioactive Dermatitis

Categorization	Biomaterials	Drug Administration	Release Kinetics/Key Parameter	Mechanisms of Action and Results	Ref
Nanotechnology for Oxidative Stress and Early Microvascular Endothelial Injury	AHP-Cur/EGCG hydrogel	Smear	EGCG release: ~95% at 48 h; Curcumin release: ~46% at 48 h; DPPH scavenging rate: ~80%	A charge-balanced network, constructed via an Alg-HA/PLL matrix, inhibits protein adsorption, reduces intracellular ROS, and shortens healing time.	[27]
	K16 Heparin Mimetic Peptide Hydrogel	Smear	DPPH scavenging: ~57.6% at 8 mg/mL; ABTS scavenging: ~65% at 100 μM; self-assembled nanofibrous 3D porous structure	An ECM-mimetic peptide enables effective ROS scavenging and pro-angiogenic microenvironmental support.	[28]
	LTP-treated S--F hydrogel (Activation of silk fibroin gels by non-thermal plasma technology)	Subcutaneous implant	Tensile strength increased by LTP treatment; β-sheet content increased; degradation rate: ~80% at 14 days	Enhances cell adhesion and improves wound healing rate via released reactive nitrogen species (RNS), though antioxidant capacity is relatively weak.	[29]
	F-NaHA hydrogel (Fullerenol-sodium hyaluronate hydrogel)	Smear	ROS scavenging: IC50 ~12 μg/mL; gram-scale production >20 g, yield >95%; particle size: ~7.5 nm; zeta potential: −52.96 mV	Fullerene-conjugated structures scavenge superoxide anions to protect β1-integrin⁺ epidermal stem cells and mitigate radiation-induced G1 arrest.	[30]
	MSC-Exo (Mesenchymal stem cell exosomes)	Intramuscular injection	miR-210 delivery; NRF2/ARE pathway activation	NRF2/ARE pathway activation, achieved via miR-210 delivery, enhances keratinocyte survival and mitochondrial function through redox regulation, while inhibiting pro-inflammatory factors.	[31]
	SP-EVs@AST gel	Smear	Sustained release over 24 h; hydrogel swelling equilibrium at 8 h; adhesive strength: ~300–400 Pa	Microalgae vesicles loaded with astaxanthin regulate the Nrf2/Keap1/HO-1/NQO1 signaling pathway, upregulate antioxidant enzymes, and downregulate pro-inflammatory factors.	[32]
	GK@TAgel (Cutaneous ECM-inspired glycopeptide hydrogel)	Smear	ROS scavenging: ~85% at 200 μg/mL; H2O2 scavenging: >80%; adhesion strength: 37.7–99.4 kPa	Eliminates radiation-induced ROS, alleviates DNA damage, induces macrophage polarization towards M2 type via mannose receptors (MR), and promotes angiogenesis.	[33]
	Chicory root extract gel	Smear	Total phenolic content: ~15 mg GAE/g; DPPH antioxidant activity: 55.72 ± 0.91%; gel possesses moisturizing and barrier-forming properties	Eliminates radiation-induced ROS, inhibits pro-inflammatory factors and cell apoptosis, and provides moisturizing effects. Raw materials are readily available with low cost.	[34]
	Au-hSiO2-Pt-TA (Janus nanomotor)	Smear	Skin permeability 12.8× higher than passive NPs; NIR-II/H2O2 dual-propelled; diffusion coefficient increases with H2O2 concentration (0–200 μM); half-life in skin: ~33 h	Achieves deep penetration through NIR-II light and H2O2 dual-propulsion, triggers CGRP-RAMP1 neuro-immune regulation to inhibit inflammatory cell recruitment, and uses tannic acid to eliminate ROS.	[35]
Immune Microenvironment Remodeling and Anti-fibrotic Materials	NLRP3-DZ@ZIF-8/TAT	Smear	Zn2⁺-dependent release over 96 h; TAT peptide enhances transdermal penetration	Cuts NLRP3 mRNA via DNAzyme, blocking inflammasome activation at the post-transcriptional level and reducing IL-1β/IL-18 release to exert anti-fibrotic effects.	[36]
	pY-Gel@GMSCs (Nap-GDFDFpDY self-assembled peptide hydrogels wrapped with gingival MSCs)	Intramuscular injection	Hydrogel concentration: 3 mg/mL in PBS, pH 7.3–7.4, with alkaline phosphatase 1 U/100 µL; ECM-mimetic scaffold; sustained paracrine effect; biodegradable and biocompatible in vivo; prevents rapid diffusion and adheres well to tissue	Leveraging a biomimetic ECM to maintain GMSCs; reduces TNF-α and IL-1β via paracrine EGFR/STAT3 pathway and decreases collagen deposition.	[37]
	Genistein	Subcutaneous injection	Dermatitis Score (Day 70): Reduce by approximately 75–80%	Inhibits radiation-induced p21/waf1 and α-smooth muscle actin, preserves K15-positive adult skin stem cells, and reduces neutrophil/macrophage infiltration.	[38]
	Antibiotic-loaded keratin hydrogel	Smear	Sustained release over 7–18 days; ciprofloxacin/cefazolin: ~100% release at 7 days; neomycin: ~20% release	Regulates the surface microenvironment through the inherent repair activity of keratin and local sustained release of antibiotics, but lacks active anti-fibrotic regulation.	[39]
	DAM	Subcutaneous implant	Pore size: 50–200 μm (based on prior DAM characterization); porosity: ~85%; Volume retention: 35.67 ± 5.1% at 8 weeks post-injection (MRI, n=5); Injection performed 2 weeks prior to irradiation; 30 Gy delivered as 6×5 Gy fractions over 12 days	Contains adipogenic proteins and growth factors; promotes adipocyte regeneration and angiogenesis, down-regulates pro-fibrotic pathways, and improves radiation-induced fibrosis.	[40]
	Tat-PYC-Smad7	Local injection	Sustained release over 14 days; no systemic absorption; no antidrug antibody formation in canine model	Delivers Smad7 protein locally, simultaneously inhibiting NF-κB, TGF-β, and STAT3 signaling pathways to alleviate inflammation, oxidative damage, and fibrosis.	[41]
Nanocomposite Materials	MS-CeO2-miR129 (Mesoporous silica-cerium oxide nanocomposites)	Subcutaneous injection	Specific surface area: ~450 m2/g; Ce3⁺/Ce4⁺ redox cycling	Ce3⁺/Ce4⁺ redox cycling regulates hypoxia, while miR129 regulates the Chk2 pathway by targeting RAD17 to promote DNA damage repair, potentiating tumor suppression and reducing off-target toxicity.	[42]
	PDA-NPs@MSC-SEV	Intramuscular injection	PDA-NPs photothermal conversion efficiency: ~40%; hydrogel adhesion strength: ~20 kPa; degradation: complete at 96 h	PDA-NPs provide free radical scavenging and photothermal antibacterial properties; MSC-sEV regulates vascular inflammatory factors via paracrine miRNA, synergistically down-regulating TNF-α/IL-6 and up-regulating IL-10/TGF-β to promote angiogenesis.	[43]
	miR181a@EM-HB-IFI6	Subcutaneous injection	miR181a loading rate:~81% complete wound healing: ~24 days	HB increases wound oxygen content; IFI6 activates the SSBP1/HSF1 pathway to alleviate oxidative stress and inflammation; miR181a reduces radiation sensitivity by inhibiting PTEN. Accelerates healing and increases neovascularization.	[44]
	IFI6-PDA@GO/SA nanomaterials	Smear	GO specific surface area: ~800 m2/g; complete wound healing: ~26 days	IFI6 activates the SSBP1/HSF1 signaling axis to boost angiogenesis and granulation; GO exhibits antibacterial activity; SA provides moisturizing properties, establishing a comprehensive repair mechanism.	[45]
	SF/PF@DOX + PTA@Au-GA (Biodegradable hydrogel + Antioxidant bioadhesive)	Internal implant + Smear	O2 release: ~7 mg/L; DOX release: 26.9–86.0% at 30 days; GA release under NIR: ~87%	SF/PF@DOX continuously releases oxygen and DOX to improve tumor hypoxia and radiosensitivity. PTA@Au-GA enables photothermal-triggered spatiotemporal release of gallic acid for enhanced ROS scavenging, promoting angiogenesis and tissue repair.	[46]
	SPM hydrogel (MoS2 nanosheet-doped double network hydrogel)	Smear	MoS2 ~0.20 wt%; antioxidant ~70%; adhesion 4–9 kPa; water content >80%	MoS2 nanoplatelets possess antioxidant properties, effectively alleviating excessive ROS and reducing oxidative stress to prevent radiation-induced skin tissue damage.	[47]

Figure 1.

Clinical demand and pathogenesis of radiation dermatitis. (a) Up to 95% of tumor patients experience moderate to severe skin reactions, leading to radiotherapy discontinuation, financial strain, and psychological burden. Thus, novel treatment strategies are urgently needed. (b) The pathogenesis progresses along a timeline: oxidative stress acts as the central driver, triggering immune microenvironment imbalance and persistent inflammation. This subsequently damages microvascular endothelial cells, ultimately culminating in cutaneous fibrosis.

Pathogenesis of Radiation Dermatitis

Oxidative Stress

Radiation directly damages basal layer stem and progenitor cells,⁸ impairing proliferation, migration, and keratinization; excessive ROS trigger mitochondrial apoptosis, endoplasmic reticulum stress,⁹ and the mitogen-activated protein kinase (MAPK) activation, causing cell death.^10,11 ROS upregulate nuclear receptor coactivator 4 (NCOA4) to mediate ferritinophagy, which leads to free iron accumulation drives lipid peroxidation and ferroptosis.¹² Elevated ROS act as danger-associated molecular patterns (DAMPs), activating macrophage Toll-like receptors (TLRs), the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway, and the NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome,^13,14 inducing their polarization towards M1-type macrophages (M1). Radiation causes mitochondrial dysfunction, leading to mitochondrial DNA (mtDNA) damage. MtDNA damage activates the cGAS–STING pathway and downstream inflammatory signaling.¹³ M1 macrophages release pro-inflammatory factors such as interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α), activate the nuclear factor-κB (NF-κB)/MAPK pathway, and promote NLRP3 inflammasome can cleave mature IL-1β,¹⁵ synchronously amplifying the inflammatory response.^16,17 Radiation exacerbates oxidative damage by inhibiting GCH1/BH4 (GTP cyclo-hydrolase 1/5,6,7,8-Tetrahydrobiopterin) synthesis, leading to nitric oxide synthase(NOS) uncoupling.¹⁸

Imbalance of the Immune Microenvironment

The M2-type macrophages (M2) secrete anti-inflammatory cytokines and growth factors to promote tissue regeneration and vascular stability.^19,20 Radiation disrupts the M1–M2 macrophage balance, blocking M1-to-M2 transition.^21,22 M2 macrophages secrete transforming growth factor-β (TGF-β) and platelet-derived growth factor (PDGF), persistently activating Smad2/3 (Sma- and Mad-related protein 2/3) signaling to drive fibroblast-to-myofibroblast differentiation, excessive type I collagen deposition, and skin fibrosis.¹³ Although M2-derived interleukin-10 (IL-10) is anti-inflammatory, it fails to suppress the upstream cGAS-NLRP3 inflammatory cascade under polarization imbalance,¹⁴ fueling a vicious cycle of chronic inflammation and aberrant collagen deposition that drives advanced radiation-induced skin damage.^23,24 Recent studies show that radiotherapy disrupts the skin microbial barrier by depleting cutaneous microbiota, reducing lactobacilli, and promoting Staphylococcus aureus overgrowth—causing epidermal barrier dysfunction.²⁵

Damage to Microvascular Endothelial Cells

Radiation directly damages dermal microvascular endothelial cells,^26,48 and surviving endothelial cells release TNF-α and IL-1β, triggering microvascular collapse and basement membrane thickening.^49,50 Radiation also induces endothelial–mesenchymal transition (EndMT),⁵¹ driving TGF-β–dependent loss of endothelial markers and conversion to myofibroblasts that deposit excess extracellular matrix (ECM), worsening chronic radiation dermatitis.⁵² Ionizing radiation activates acid sphingomyelinase (ASMase), leading to the generation of ceramide-enriched lipid rafts that promote clustering of CD95 (cluster of differentiation 95) death receptors—thereby accelerating endothelial cell apoptosis.^53,54

Cutaneous Fibrosis

The skin contains diverse fibroblast subpopulations with distinct origins and functions (Figure 2). Upon radiation exposure, these fibroblasts undergo phenotypic changes that drive excessive ECM deposition and progressive fibrosis (Figure 3). Radiation can cause fibroblasts to transform into myofibroblasts, which continuously synthesize ECM, especially type I collagen and α-smooth muscle actin, accelerating fibrosis.⁵⁵ ECM accumulation in the dermis stiffens skin and impairs elasticity; microvascular structure also remodels.⁵⁶ TGF-β activates fibroblasts and drives radiation-induced fibrosis.^57,58 TGF-β is significantly expressed in irradiated skin tissue compared to normal tissue,⁵⁸ continuously driving fibroblast activation through the classical Smad2/3 pathway, and synergistically amplifying the fibrosis signal with PDGF.^59,60 Radiation upregulates Dickkopf3 (DKK3) in keratinocytes, activating TGF-β/Wnt signaling and driving epidermal hyperproliferation, ROS accumulation, M2 macrophage polarization, and myofibroblast activation, culminating in skin fibrosis⁵² (Figure 4).

Figure 2.

Origins and differentiation of fibroblast subpopulations in skin wound healing. Heterogeneity of fibroblast populations in skin wound healing. Fibroblasts in the skin are derived from multiple sources, including papillary fibroblasts, reticular fibroblasts, hypodermal fibroblasts, pericytes, adipocytes, fascia, circulating cells, and other proposed sources such as dermal En1 lineage-positive and -negative fibroblasts. Under the stimulation of wound-associated signals (WNT, TGF-β, IL, TNF, PDGF), these fibroblast subsets contribute to myofibroblast formation and wound healing. Adnexal regeneration is also observed in large wounds. This schematic summarizes the cellular origins and differentiation pathways of fibroblast subpopulations involved in skin repair and fibrosis.

Figure 3.

Cellular and extracellular matrix events during fibrotic remodeling of radiation-induced skin injury. Schematic illustration of extracellular matrix remodeling during the fibrotic phase of radiation-induced skin injury. Following radiation exposure, fibroblasts undergo phenotypic conversion into myofibroblasts, which actively synthesize and deposit extracellular matrix components, predominantly type I and type III collagen. Macrophages undergo apoptosis and exit the wound site, while matrix metalloproteinases (MMPs) mediate the degradation and reorganization of the existing collagen-based ECM. The balance between collagen deposition and degradation determines the progression of tissue fibrosis. This figure depicts the key cellular events and ECM dynamics during the chronic remodeling phase of radiation dermatitis.

Figure 4.

Pathogenesis of radiation dermatitis. This diagram illustrates the four major pathological pathways involved in radiation dermatitis. In the figure, standard arrows indicate the sequence of biological events, transformation processes, or promoting effects, whereas T-shaped (blunt-ended) lines indicate inhibitory or blocking effects. The specific mechanisms include: (1) Oxidative stress: ROS target and destroy basal stem cells and vascular structures; (2) Cutaneous fibrosis: Pro-inflammatory and pro-fibrotic cytokines promote fibroblast transformation and extracellular matrix secretion; (3) Immune microenvironment imbalance: Mutual inhibition and imbalanced differentiation between M1 and M2 macrophages; and (4) Microvascular endothelial damage: Radiation induces endothelial cell apoptosis and functional abnormalities, ultimately leading to tissue damage.

Status of Radiation Dermatitis Treatment

Current therapeutic approaches, including pharmacological treatments such as corticosteroids, natural compounds, and growth factors, as well as non-pharmacological interventions like hyperbaric oxygen therapy, low-intensity laser therapy, and surgery, can to some extent promote the repair of radiation dermatitis.¹³ However, clinical applications face certain limitations.⁶¹ For instance, Bostrom,⁶² Shukla,⁶³ and others have reported that topical corticosteroids show moderate efficacy in preventing and treating radiation-induced dermatitis, but they fail to significantly alleviate severe skin lesions and may cause adverse effects such as skin atrophy, moist desquamation, and secondary bacterial infections.^64,65 Platelet-derived and fibroblast growth factors inhibit skin fibrosis by blocking the TGF-β/Smad2/3 pathway, suppressing ECM synthesis, and promoting anti-fibrotic macrophage polarization—yet they may also stimulate tumor growth.⁶⁶ Hyperbaric oxygen therapy and low-intensity laser therapy are effective for radiation-induced dermatitis, but their use is limited by high cost, poor tolerance of hyperbaric conditions, and interindividual variability.^67,68 In summary, conventional treatments are limited by poor targeting ability, narrow mechanism of action, systemic toxicity, tumor safety concerns, and insufficient clinical evidence. These treatments only alleviate superficial skin symptoms and cannot prevent radiation-induced damage from progressing to fibrosis.^69,70 To enhance the therapeutic effect, effective and multi-functional interventions are urgently needed.⁷¹ In recent years, nanotechnology has emerged, which can enhance drug absorption, regulate oxidative stress and the tissue microenvironment, simultaneously enhance radiotherapy sensitization and skin lesion repair, and achieve local administration to reduce systemic side effects, thus addressing the limitations of traditional therapies.^47,72 This has opened up new avenues for the safe and effective intervention in radiation dermatitis and demonstrates extensive research potential.³⁶

Application of Nanotechnology in the Treatment of Radiation Dermatitis

Nanotechnology for Oxidative Stress and Early Microvascular Endothelial Injury

Radiation-induced oxidative stress disrupts the oxidative balance within the wound, and its continuous development can lead to severe cellular and vascular damage.⁷³ Therefore, enhancing the skin’s antioxidant capacity and eliminating wound inflammation are important measures for successful treatment of radiation dermatitis.¹⁸ In recent years, targeted oxidative stress nanotechnology has reduced ROS, simultaneously blocking upstream oxidative damage, and alleviating secondary microvascular and endothelial cell lesions.⁷⁴

Polyphenolic compounds, such as free gallic acid (GA), can upregulate antioxidant genes and promote keratinocyte and endothelial cell migration through the focal adhesion kinase (FAK), c-Jun N-terminal kinase (JNK), and extracellular signal-regulated kinase (Erk) pathways. However, their poor water solubility and weak skin permeability make effective vascular repair difficult to achieve in the body.^75,76 Sodium alginate/hyaluronic acid-polylysine hydrogel co-loaded with curcumin and epigallocatechin gallate (AHP-Cur/EGCG) polyphenols rapidly scavenges ROS, exhibiting anti-inflammatory, pro-angiogenic, protein-resistant, and antibacterial adhesion properties, along with excellent blood compatibility.²⁷ Peptides and biomimetic peptide hydrogels: Antioxidant heparin-mimetic peptide hydrogel (K16, KYKYEYEYAGEGDSS-4SA) mimics the ECM mechanism and eliminates ROS, promoting angiogenesis.²⁸ Liquid-type nonthermal atmospheric plasma enhanced regenerative potential of silk–fibrin composite gel (LTP-treated S–F hydrogel) can alleviate oxidative damage by releasing reactive nitrogen species (RNS), assists in endothelial proliferation and ECM remodeling, but its antioxidant capacity is relatively weak.²⁹ As a carbon-based antioxidant hydrogel, fullerene alcohol has broad-spectrum ability to eliminate ROS and RNS, and can increase the survival rate of skin cells after irradiation. Animal experiments have verified that it has no skin irritation, organ accumulation, or systemic toxicity risks in the short term.³⁰ Existing randomized controlled clinical trials have confirmed that it can alleviate acute radiation dermatitis and delay the progression of skin lesions, but the sample size is small and there are limitations such as lack of long-term effectiveness and safety assessment.⁷⁷ Among vesicle-delivery type materials, mesenchymal stem cell-derived exosomes (MSC-Exo) can activate the nuclear factor erythroid 2-related factor 2 (Nrf2) antioxidant pathway adaptively, and simultaneously inhibit the secretion of pro-inflammatory factors such as TNF-α and IL-1β. However, the administration method is intradermal injection, and patient acceptance is low.³¹ Cui et al³² isolated extracellular vesicles (EVs) from the natural microalgae spirulina platensis (SP) and engineered them by loading astaxanthin (AST) into SP-EVs, resulting in the formation of SP-EVs@AST. To optimize topical administration, SP-EVs@AST were incorporated into a self-assembled hydrogel composed of aldehyde-functionalized hyaluronic acid (HA-CHO) and carboxymethyl chitosan (CMCS), forming a skin radiation protection dressing (SP-EVs@AST gel). SP-EVs@AST gel microalgae vesicles loaded with AST regulate the Nrf2/Keap1 (Kelch-like ECH-associated protein 1)/HO-1 (heme oxygenase-1)/NQO1 (NAD(P)H quinone dehydrogenase 1) signaling pathway, upregulate antioxidant enzymes, and downregulate pro-inflammatory factors.³² A cutaneous ECM-inspired glycopeptide hydrogel (GK@TA^gel) can eliminate radiation-induced ROS, alleviate DNA damage, induce macrophages to polarize towards the M2 type through mannose receptors (MR), promote angiogenesis, regulate the chronic inflammatory microenvironment, and facilitate wound healing in radiation dermatitis wounds.³³ The representative product of the plant extract category, chicory root extract gel, contains components such as polyphenols, sesquiterpene lactones, inulin, mucus, minerals and vitamins.^78,79 It can eliminate radiation-induced ROS, inhibit pro-inflammatory factors, and inhibit radiation-induced cell apoptosis.⁸⁰ At the same time, it has a moisturizing effect.⁸¹ Compared with other hydrogel materials, its raw materials are readily available, the cost is low, and a three-blind randomized controlled clinical study has been completed for breast cancer radiotherapy patients, with a good safety profile. However, the sample size is small and long-term follow-up data are lacking.³⁴

Recently, Zhang et al³⁵ reported near-infrared-II (NIR-II) light and endogenous H₂O₂ dual-propelled Janus nanomotor (Au-hSiO₂-Pt-TA), which achieves deep penetration through self-heating and self-electrophoresis, and has 12.8 times higher skin permeability than passive nanoparticles. This nanomotor triggers neuro-immune regulation through the calcitonin gene-related peptide/receptor activity-modifying protein 1 (CGRP-RAMP1) axis, inhibits the recruitment and migration of inflammatory cells, induces macrophages to polarize towards a repair phenotype, and uses the loaded tannic acid to eliminate ROS. It shows efficient therapeutic effects in BALB/c mice and SD rat models. However, this study is still in the preclinical animal validation stage, and the clinical practicality of the NIR-II laser equipment and multi-step synthesis process needs to be evaluated.

In the antioxidant aspect, fullerene alcohol has a broad-spectrum ability to eliminate ROS/RNS,⁷⁷ while SP-EVs@AST and MSC-Exo both possess the ability to activate the endogenous antioxidant pathway of Nrf2.^31,32 In the microvascular protection aspect, K16, SP-EVs@AST, LTP-treated S–F hydrogel and GK@TA^gel can all promote the formation of endothelial lumens,^28,29,32,33 while fullerene alcohol, AHP-Cur/EGCG, GA and chicory root extract gel lack direct intervention on endothelial damage.^27,30,75,76 In the translation stage, fullerene alcohol and chicory root extract gel have completed randomized controlled trial (RCT) for breast cancer radiotherapy patients, but the sample size is small and there is a lack of long-term follow-up data, and the other materials are limited to animal experiments.^77–79 The recently emerged Janus nanomotor (Au-hSiO₂-Pt-TA) achieves physical deep transdermal penetration through dual drive by NIR-II light and H₂O₂, and introduces the neural-immune regulatory axis to collaboratively eliminate ROS, providing a physical-biological combined intervention paradigm for the treatment of radiation dermatitis. However, its clinical operability remains to be verified.³⁵

Immune Microenvironment Remodeling and Anti-Fibrotic Materials

Acute-stage oxidative stress is the initiating factor of radiation-induced dermatitis.⁸² However, the persistent and unhealed condition of the disease can lead to fibrosis, suggesting that the treatment strategy should not only “antioxidize” but also target and regulate the “immune-fibrosis” process.⁵²

NLRP3-DZ@ZIF-8/TAT (NLRP3-targeting DNAzyme encapsulated in zeolitic imidazolate framework-8 and modified with Trans-activator of Transcription peptide) cuts NLRP3 mRNA through DZ, blocking the activation of the inflammasome at the post-transcriptional level, and reducing the release of IL-1β/IL-18 (interleukin-18).⁸³ This material mainly exerts its anti-fibrotic effect by blocking the upstream pathways.³⁶ Nap-GDFDFpDY (pY-Gel), a Ca²⁺-responsive supramolecular hydrogel formed by self-assembling phosphorylated peptides, encapsulates gingiva-derived mesenchymal stem cells (GMSCs) to yield pY-Gel@GMSCs. The pY-Gel@GMSCs reduce TNF-α and IL-1β through the paracrine EGFR/STAT3 (epidermal growth factor receptor/signal transducers and activators of transcription 3) pathway and decrease collagen deposition.⁸⁴ In the mouse model, they achieve multiple repair effects such as promoting proliferation, promoting migration, promoting DNA repair, anti-inflammation, and anti-fibrosis.³⁷ Genistein can inhibit the radiation-induced cyclin-dependent kinase inhibitor 1 (p21/CDKN1A) and α-smooth muscle actin, preserve keratin 15 (K15)-positive adult skin stem cells, and simultaneously reduces the infiltration of neutrophils and macrophages induced by radiation, and alleviates the chronic inflammatory microenvironment.³⁸ However, this material is only administered by subcutaneous injection, and there are concerns regarding the tumor safety related to estrogen-like effects.⁸⁵ The antibiotic-loaded keratin hydrogel regulates the surface microenvironment of radiation dermatitis through the inherent repair activity of keratin and the local sustained release of antibiotics, but it lacks active regulation of microenvironment remodeling and fibrosis process.³⁹ Decellularized adipose matrix (DAM) contains adipogenic proteins and growth factors, which may contribute to the paracrine function of autologous fat transfer (AFT),^86,87 thereby promoting adipocyte regeneration, angiogenesis, down-regulating the pro-fibrotic pathways through paracrine signaling, regulating collagen structure and dermal thickness.^88–90 In an animal experiment, it can improve radiation-induced fibrosis and lead to the covered skin retaining the histological and biomechanical characteristics of normal unirradiated skin.⁴⁰ Boss et al created a truncated human Smad7 protein fused with the cell-penetrating Tat tag (Tat-PYC-Smad7).⁹¹ Tat-PYC-Smad7 delivers the Smad7 protein locally, simultaneously inhibiting the NF-κB, TGF-β⁹² and STAT3⁹³ signaling pathways, thereby alleviating inflammation, oxidative damage and fibrosis. In canine models, it achieved a synergistic effect of inflammation regression and reduced collagen deposition. However, the sample size of the canine model is small (n = 4 per group), and there is a lack of data on the long-term safety of transdermal peptides.⁴¹

Tat-PYC-Smad7 regulates anti-fibrotic effects in the inflammatory microenvironment through multiple pathways,⁴¹ and this effect is the most clearly defined among other material pathways. These materials exhibit excellent biocompatibility. The keratin biomaterials (trade names KeraStat Cream and KeraStat Gel) derived from human hair have been cleared by the US Food and Drug Administration (US FDA) under the 510(k) mechanism for the treatment of radiation dermatitis in humans.⁹⁴ However, the long-term safety of the antibiotic-loaded materials needs further verification.³⁹ The remaining materials lack clinical translation data and long-term toxicity assessment. Genistein also raises concerns regarding its estrogen-like activity and potential tumor safety risks.⁹⁵ At the targeted regulation level, the effects of each material are relatively simple and difficult to prevent the evolution of “oxidative stress - microenvironment imbalance - fibrosis” of radiation dermatitis. To address this mechanism, the researchers turned their attention to nanocomposite materials - by integrating different functional components, achieving multi-targeted and multi-stage synergistic effects to treat radiation dermatitis.^96,97

Nanocomposite Materials

Zhou et al⁴² constructed a composite nanozyme (MS‑CeO2‑miR129) that anchors mesoporous silica (MS) nanoparticles and loads microRNA-129 (miR129) onto them.⁴⁶ This design utilizes MS as a carrier to provide a core-shell structure, enhancing the material’s circulation in wound blood vessels.⁹⁸ The cerium oxide (CeO₂) nanozyme continuously removes ROS due to the increase in Ce³⁺/Ce⁴⁺, alleviating wound hypoxia and reducing hypoxia-inducible factor-1α (HIF-1α) expression.^99,100 MiR129 regulates the checkpoint kinase 2 (Chk2) pathway by targeting radiation-sensitive 17 (RAD17), upregulating poly (ADP-ribose) polymerase (PARP) and phosphorylated histone H2AX (γH2AX) expression, and promoting DNA damage repair.¹⁰¹ This study first revealed the mechanism by which miR129 regulates radiation sensitivity through the PARP/γH2AX axis, providing a theoretical basis for the combined application of nanozymes and miRNAs in the treatment of radiation dermatitis. However, the long-term in vivo degradation and accumulation of CeO₂ remain unclear, and it has not been verified in the human body.

Fang et al⁴³ cross-linked carbohydrazide-modified gelatin (Gel-CDH) with oxidized hyaluronic acid (OHA) and encapsulated nano-sized mesenchymal stem cell-secreted small extracellular vesicles (MSC-sEV) and polydopamine (PDA)-NPs to prepare a multifunctional hydrogel (PDA-NPs@MSC-sEV). Due to its rich catechol content, PDA-NPs possess an efficient ability to eliminate free radicals and enhance the adhesion and photothermal antibacterial properties of the hydrogel.¹⁰² MSC-sEV regulate vascular inflammatory factors through paracrine miRNA, synergistically down-regulating TNF-α/interleukin-6 (IL-6) and up-regulating IL-10/TGF-β, increasing CD31 (Cluster of Differentiation 31, also known as PECAM-1) expression and promoting angiogenesis.^103,104 This hydrogel can promote wound healing and increase hair follicle and sebaceous gland regeneration in mouse models. The observation period of this study was only 15 days, and the long-term fibrosis outcome was not evaluated.⁴³

Zhou et al⁴⁴ designed a material by modifying interferon-alpha inducible protein 6 (IFI6) and microRNA-181a (miR181a) with erythrocyte membrane (EM) and hemoglobin (HB), designated as miR181a@EM-HB-IFI6. HB increases the oxygen content in the wound and inhibits the expression of HIF-1α.¹⁰⁵ EM has good biocompatibility and circulation properties.¹⁰⁶ IFI6 alleviates oxidative stress and inflammatory responses by activating the SSBP1/HSF1 (single-stranded DNA binding protein 1/heat shock transcription factor 1) pathway.¹⁰⁷ MiR181a reduces radiation sensitivity by inhibiting PTEN (phosphatase and tensin homolog deleted on chromosome ten).¹⁰⁸ In BALB/c mice, this material shortened the time to complete wound healing to approximately 24 days, down from about 44 days in the control group. It also suppressed ROS and NLRP3 expression, promoted angiogenesis, and modulated the immune microenvironment. However, the preparation process of this material is complex and it is only at the preclinical stage. Clinical translation and production present certain challenges.⁴⁴

Hao et al⁴⁵ constructed a sodium alginate/graphene oxide/polydopamine (SA/GO/PDA) composite nanomaterial loaded with IFI6 (IFI6-PDA@GO/SA). GO exhibits excellent antibacterial activity, structural stability and biocompatibility.¹⁰⁹ SA has antibacterial activity and moisturizing properties.¹¹⁰ This material also exerts a radioprotective effect through the activation of SSBP1/HSF1 by IFI6,¹⁰⁷ shortening the wound healing time in mouse models. However, GO has the characteristic of being non-biodegradable, and long-term use may pose the risk of accumulation in the body.⁴⁵

Zhang et al⁴⁶ designed a biodegradable hydrogel for implantation inside the body and an external antioxidant biological adhesive to simultaneously prevent tumor recurrence after surgery and assist in the treatment of radiation-induced skin damage after radiotherapy. The internally implanted SF/PF@DOX (silk fibroin/perfluorocarbon/doxorubicin) can continuously release oxygen and DOX around the tumor, thereby improving the tumor’s hypoxia and the sensitivity to radiotherapy.^111,112 The externally applied polythioctic acid (PTA)@Au-GA antioxidant biological adhesive undergoes mild photothermal treatment, promoting angiogenesis and tissue repair of the radiation-induced skin damage, and controlling the release of GA to eliminate free radicals.^113,114 In the mouse model, the Radiation Therapy Oncology Group (RTOG) score of the material group reached 0 on the 21st day, and it delayed the development of skin radiation damage and promoted hair follicle regeneration. This material achieves the integration of antitumor function and radiation dermatitis repair. However, its clinical application requires the simultaneous management of two systems, and the clinical operability and long-term safety of NIR photothermal therapy still need to be verified.⁴⁶

Luo et al⁴⁷ prepared a dual-network hydrogel (SPM), which was composed of SA nanofibers and polyacrylamide (PAM), and incorporated molybdenum disulfide (MoS₂) nanosheets. The SA and SPM hydrogels possess excellent mechanical properties, adhesion properties, and cell compatibility. The MoS₂ nanoplatelets have antioxidant properties, enabling the SPM to effectively alleviate excessive ROS and reduce oxidative stress.^115,116 This material can alleviate radiation-induced skin tissue damage in the SD rat model. However, this study is limited to preventive effects, and the long-term skin accumulation and safety of MoS₂ nanoplatelets have not been clarified.⁴⁷

Composite materials have achieved multi-targeted treatment for radiation-induced dermatitis. Among them, SF/PF@DOX and PTA@Au-GA simultaneously address two clinical issues: antitumor and anti-dermatitis. This provides new ideas for subsequent research.⁴⁶ However, these materials still face challenges such as complex preparation processes, quality control issues, and a lack of long-term safety data. Currently, all related studies are limited to the animal experimentation stage, and clinical adoption faces severe challenges¹¹⁷ (Figure 5).

Figure 5.

Therapeutic mechanisms of novel biomaterials in radiation dermatitis. This diagram illustrates a phase-specific therapeutic strategy aligned with the disease timeline. Downward-curved arrows indicate that the four pathological drivers (oxidative stress, immune imbalance, microvascular damage, and fibrosis) collectively cause skin injury. The upward-pointing arrows at the bottom indicate that specific biomaterials are applied to target their corresponding phases. Specifically, antioxidant biomaterials (eg, fullerene, gallic acid) treat the early phase; immunomodulatory biomaterials (eg, Tat-PYC, pY-Gel@GMSCs) target the middle phase; and anti-fibrotic biomaterials (eg, anti-fibrotic nanomaterials, ECM remodeling materials) address the late phase.

Clinical Translation and Future Perspectives of Nanomaterials in the Treatment of Radiation Dermatitis

Although various nanomaterials have shown promising therapeutic effects in preclinical models, their clinical application in the treatment of radiation dermatitis is still in its infancy.¹¹⁷ Among all the materials discussed, only keratin gels (KeraStat ointment and KeraStat hydrogel) have received 510(k) approval from the US FDA for the treatment of radiation dermatitis.⁹⁴ However, keratin-based materials carrying antibiotics still lack reliable clinical data.⁸⁴ Fullerene alcohol and chicory root gel have only completed small-sample single-center randomized controlled trials (RCTs), with no long-term follow-up data, and have not been officially registered for clinical trials. Moreover, the existing experimental designs often have difficulty accurately quantifying and comparing the severity of radiation dermatitis damage, and most assessment criteria are susceptible to the variability among raters.¹¹⁸ The challenges faced in the translation of preclinical research to clinical practice are as follows:

Safety assessment remains the most prominent shortcoming at present.^23,45,119 All materials lack long-term toxicity data, and the risk of in vivo accumulation of non-degradable components such as GO and CeO₂ has not been fully studied.^42,45 Among protein and cell-derived components, only Tat-PYC-Smad7 has been reported to have no antibody formation against drugs.⁴¹ MSC-sEV and IFI6 can promote cell survival and proliferation, but their impact on tumor risk has not yet been evaluated.^120,121 Flavonoids with similar estrogenic activity may pose potential risks in hormone-sensitive cancers.¹²² In the future, a safety evaluation guideline for radiation dermatitis nanomaterials can be established, clearly defining issues such as in vivo accumulation and metabolism, immunogenicity, and tumor safety. Additionally, the preparation process is complex.¹²³ Composite nanomaterials require multiple steps of synthesis, extraction of biological components, and precise control of nanoscale structure, and batch consistency and large-scale production face difficulties.^124,125 Therefore, it is necessary to develop a simple, controllable and highly consistent synthesis method across batches, while also ensuring the safety and effectiveness of the materials. The lack of clarity in the clinical regulatory pathway is another issue that has been underestimated. Composite nanomaterials formed by combining synthetic materials with bioactive biological agents have ambiguous classification and regulatory categorization, making it difficult to fully incorporate them into the existing regulatory framework.¹²⁶ Therefore, those materials that have accumulated sufficient preclinical data can be advanced to the stage of validation in large animal models and the early clinical trials. Standardized clinical trial design, unified endpoint indicators, and long-term follow-up plans facilitate the accumulation of evidence and cross-study comparisons. The preclinical models have certain limitations. Most studies use young, healthy rodents in single-dose radiation models—failing to recapitulate clinical realities like aging, comorbidities, and repeated radiation exposure.^127,128 The canine model used to test Tat-PYC-Smad7 has made progress, but its small sample size (n=4 per group) and single-center design limit the generalizability of the results.⁴¹ Most studies lack systematic dose optimization, leaving the optimal concentration and dosing frequency undefined.¹¹⁷ In the future, the sample size can be increased and different disease and age models can be adopted to more accurately evaluate the efficacy of the materials in clinical scenarios. Collaborative treatment strategies with radiosensitization can be developed using nanotechnology to further enhance the therapeutic effect.⁴⁶ The clinical application of nanotechnology requires the collaborative efforts of experts from multiple disciplines, including specialists in materials science, life science, medical science, and pharmacy, to jointly accelerate the clinical translation of nanotechnology from the laboratory to clinical practice, thereby promoting the development of safe, effective and precision-based methods for the prevention and management of radiation-induced skin damage.

Conclusions

Radiation dermatitis is a common complication for approximately 95% of radiotherapy patients, yet traditional treatments have limited effectiveness. Nanomaterials have advantages in eliminating ROS, regulating the immune microenvironment, protecting microvessels, and resisting fibrosis. This article systematically reviews the multi-level strategies ranging from direct antioxidant materials to multi-targeted composite materials: Fullerene alcohols in direct antioxidant materials have provided preliminary clinical evidence. In immune microenvironment materials, Tat-PYC-Smad7 intervenes in chronic inflammation and fibrosis through multiple pathways in a synergistic manner. Composite materials achieve multi-targeted collaborative repair. However, most of the materials are still at the preclinical stage. The clinical transformation faces several bottlenecks such as the lack of long-term safety data, complex preparation processes, ambiguous regulatory paths, and concerns about tumor safety. Future efforts should coordinate the advancement of standardized safety assessments, scalable manufacturing processes, standardized clinical trial designs, material adaptation based on pathological stages, and nanomaterials combining multiple targets with radiation sensitization to facilitate the translation of nanomaterials from laboratory research to clinical applications.

Funding Statement

This study was supported by the Sichuan Province Natural Science Youth Foundation (No. 26QNJJB2804), the Luzhou Municipal Science and Technology Bureau’s University-Enterprise Joint Project (No. 2023LZXNYDJ053) and Southwest Medical University Undergraduate Innovation Training Programme (S202410632159).

Data Sharing Statement

The data supporting the results of this study can be obtained by the corresponding authors Zongjunlin Liu (L.Z.) and Tingting Wang (T.W.) upon reasonable request. The chart data, core conclusions of the literature review, and related data on material characteristics involved in this study have all been organized and archived in accordance with Taylor & Francis’ “Data Sharing Policy upon Reasonable Request” to ensure compliance with academic norms and data sharing requirements.

Consent for Publication

All authors have given their consent for publication.

Disclosure

All authors report no conflicts of interest in this work.