Dental pulp stem cell–derived exosomes attenuate psoriatic inflammation by restoring epithelial redox homeostasis via a miR-1246/miR-17-3p–GPX2–NF-κB axis

Abstract

Background

Psoriasis is driven by sustained epidermal inflammation tightly coupled to dysregulated redox homeostasis. Although current systemic therapies are effective, their long-term use is limited by safety concerns. Dental pulp stem cell–derived exosomes (DPSC-Exo) have emerged as promising immunomodulatory, cell-free therapeutics, yet their role in regulating epithelial redox–inflammatory balance remains undefined.

Methods

The therapeutic effects of DPSC-Exo were evaluated using an imiquimod-induced mouse model of psoriasis, ex vivo human skin explants, and M5-stimulated primary human keratinocytes. Transcriptomic profiling, immunostaining, and gain- and loss-of-function analyses were performed to define the underlying molecular mechanisms.

Results

Topical administration of DPSC-Exo markedly reduced epidermal hyperplasia, neutrophil infiltration, angiogenesis, and expression of key psoriatic mediators, including IL-23 A, IL-17 A, and antimicrobial peptides. These effects were consistently reproduced in human skin explants and keratinocyte models. RNA-sequencing identified glutathione peroxidase 2 (GPX2), a key epithelial antioxidant enzyme, as a prominently upregulated target following DPSC-Exo treatment. Restoration of GPX2 suppressed NF-κB activation and downstream cytokine production, whereas GPX2 silencing abolished the protective effects of DPSC-Exo. Mechanistically, two exosomal microRNAs, miR-1246 and miR-17-3p, were required for GPX2 induction and mediated the majority of the observed anti-inflammatory responses.

Conclusions

These findings identify a previously unrecognized miRNA–GPX2–NF-κB axis through which DPSC-Exo restore epithelial redox–inflammatory homeostasis. Our study supports DPSC-Exo as a promising cell-free therapeutic candidate for psoriasis and highlights epithelial redox regulation as a potentially targetable mechanism for inflammatory skin diseases.

Graphical Abstract

Supplementary Information

The online version contains supplementary material available at 10.1186/s13287-026-05055-9.

Background

Regenerative medicine has emerged as a promising therapeutic avenue in recent years [1]. Among the different types of stem cells, adult stem cells are particularly attractive because of their accessibility, low immunogenicity, and established safety profile [2]. Dental pulp stem cells (DPSC), a mesenchymal stem cell (MSC) population of ectodermal origin, can be readily obtained from extracted teeth and exhibit strong tissue repair and immunoregulatory capacities [3, 4]. Beyond their potential for cell replacement, adult stem cells exert therapeutic effects through the secretion of bioactive vesicles and soluble factors that can be standardized for clinical use. Increasing evidence indicates that the therapeutic effects of stem cells are mediated not only by direct cell replacement but also through paracrine signaling [5, 6]. Exosomes, nanosized vesicles (30–150 nm) secreted by stem cells, are key paracrine mediators that deliver bioactive cargo, including proteins and microRNAs, to regulate recipient cell behavior [7, 8]. Compared with other MSC-derived exosomes (MSC-Exo), DPSC-derived exosomes (DPSC-Exo) have demonstrated particularly strong immunomodulatory activity and efficient cellular uptake [9, 10]. DPSCs are also readily available and ethically acceptable, making DPSC-Exo a practical candidate for developing scalable, cell-free therapeutic products.

Psoriasis is a chronic inflammatory disease characterized by autoimmune-driven inflammation and epidermal hyperplasia that results in red scaly plaques that typically affect the extensor surfaces of the limbs, scalp, and lower back, and may also involve joints and internal organs in severe cases [11]. Beyond its cutaneous manifestations, psoriasis is an important risk factor for cardiovascular disease [12, 13]. With a global prevalence of 3–10%, psoriasis imposes a substantial burden on health and the quality of life of patients [14]. Current treatments (topicals, phototherapy, systemic immunosuppressants, and biologics) are effective for many psoriasis patients but are limited by adverse effects, high cost, and uncertain long-term safety, underscoring the need for new, durable, and safer therapeutic strategies [15]. Stem-cell-derived exosomes (MSC-Exo) have recently emerged as a promising acellular approach for inflammatory skin diseases. Studies using adipose- or bone-marrow-derived exosomes have shown reductions in psoriatic cytokines such as IL-17 and IL-23 and preliminary therapeutic benefit [16, 17]. However, the mechanisms by which exosomes modulate epithelial inflammation remain incompletely understood, particularly in the context of oxidative stress, which sustains chronic skin inflammation. Although DPSC-Exo are known to promote cutaneous repair and to modulate inflammation in oral tissues [18, 19], their role in cutaneous inflammation has not been examined. Given their strong immunomodulatory capacity and ease of preparation, DPSC-Exo provide an opportunity to explore how stem-cell-derived vesicles might restore epithelial oxidative and inflammatory balance. Understanding this mechanism could inform the development of safe and durable acellular treatments for psoriasis and related skin disorders.

Glutathione peroxidase 2 (GPX2) is an antioxidant enzyme predominantly expressed in epithelial tissues [20, 21], where it protects against oxidative stress and modulates inflammatory signaling. The reduced expression of GPX2 has been linked to aberrant NF-κB activation and the excessive production of pro-inflammatory cytokines, processes central to the pathogenesis of psoriasis [22–25]. The function of GPX2 in psoriasis, and its potential regulation by exosome-based interventions, has not been previously investigated. Because oxidative stress and inflammation reinforce each other, restoring GPX2 activity may interrupt this cycle and help re-establish tissue homeostasis.

In this study, we examined the therapeutic potential of DPSC-Exo in psoriasis using in vivo, ex vivo, and in vitro models. We identified a previously unrecognized miR-1246/miR-17-3p–GPX2–NF-κB axis through which DPSC-Exo restore redox balance and suppress epithelial inflammation. Transcriptomic profiling and functional validation revealed that DPSC-Exo alleviate psoriatic inflammation by restoring GPX2 expression and suppressing NF-κB signaling, an effect mediated at least in part by the exosomal delivery of miR-1246 and miR-17-3p. These findings provide a mechanistic basis for the use of DPSC-Exo to regulate epithelial oxidative–inflammatory homeostasis and support their development as an accessible, acellular therapeutic approach for psoriasis and other epithelial inflammatory disorders.

Methods

Study design

The purpose of this study is to clarify the role of dental pulp stem cell-derived exosomes (DPSC-Exo) in regulating epithelial oxidative inflammation, to evaluate their specific anti-inflammatory and skin tissue repair-promoting therapeutic potential in a psoriasis model, to elucidate the molecular mechanisms of the treatment, and to extend the therapeutic potential of dental pulp stem cells beyond oral tissue regeneration. The anti-inflammatory function and potential molecular mechanism of DPSC-Exo in in vitro psoriasis cell models were determined through qRT-PCR, Western blot, and RNA-seq. All assays were performed on biological replicates as described in the figure legends. The IMQ-induced mouse psoriasis model and the ex vivo cultured psoriasis model were used to analyze the in vivo therapeutic potential of DPSC-Exo and its ability to repair skin tissue. Each in vivo experiment used three mice (8 weeks old) per group, randomly assigned to experimental groups. All procedures were approved by the Institutional Ethics Committee and conducted according to GB/T35892-2018 guidelines and ARRIVE guidelines 2.0. This plan has been reviewed and approved by Ningbo Stomatology Hospital and the Hospital’s Ethics Committee.

Cell cultivation and identification

A total of 12 discarded healthy impacted third molars were collected from six patients aged 18–25 years undergoing tooth extraction. Dental pulp tissues were extracted, washed, and cut into approximately 1 mm fragments. The tissues were digested with 2.5 mg/mL collagenase III and 2.5 mg/mL Dispase II, followed by the termination of digestion, centrifugation, and resuspension. The resulting cell suspension was plated in culture dishes and incubated at 37 °C. DPSCs were maintained in high-glucose MEM-α medium supplemented with 10% fetal bovine serum (FBS) and 1% penicillin–streptomycin.

For multipotency verification, osteogenic and adipogenic differentiation was induced using osteogenic induction solution (Oricell #HUXXC-90021) and adipogenic induction solution (Oricell #HUXXC-90031), respectively. Osteogenesis and adipogenesis were confirmed by Alizarin Red (Solarbio # G1452) and Oil Red O (Solarbio #G1260) staining, respectively.

Flow cytometry was performed to identify surface markers of DPSCs. A total of 1 × 10⁷ cells were incubated with fluorescent dye–conjugated antibodies against CD44 (BioLegend #103019), CD105 (Proteintech# APC-FcA98013), CD90 (Invitrogen #12-0909-42), CD45 (BioLegend #304005), CD19 (BioLegend #302215), and CD14 (Invitrogen #45-0149-42) at 4 °C in the dark for 30 min, washed with PBS, and then analyzed.

Discarded foreskin tissues from surgery were collected for the isolation and culture of primary human keratinocytes as previously described [26].

Isolation and characterization of DPSC-exo

DPSCs were cultured in high-glucose MEM-α medium supplemented with 10% exosome-depleted FBS (Umibio #UR50202) until they reached ~ 80% confluence. Conditioned medium was collected and centrifuged at 3,000 g for 10 min at 4 °C. ECS reagent (Umibio #UR52121) was added and incubated at 4 °C for 12 h, followed by centrifugation at 10,000 g for 60 min. The pellet was further purified using an EPF column (3,000 g, 10 min, 4 °C) to obtain exosomes, which were stored at − 80 °C. Exosomes derived from different donor cells were analyzed separately.

Exosomes were characterized by: (1) TEM for morphology; (2) NTA (ZetaView) for size distribution; and (3) Western blotting for exosomal markers CD63 (Abcam #ab216130), TSG101 (Abcam #ab125011), and CD81 (Abcam #ab79559), with Calnexin (Abcam #ab22595) used as a negative control.

Labeling of exosomes and uptake

Exosomes were labeled with PKH67 fluorescent dye (Umibio #UR52303) for 10 min, after which excess dye was removed. Labeled exosomes were co-cultured with primary human keratinocytes for 24 h, followed by F-actin staining and fluorescence microscopy (Olympus BX53-DP80).

For in vivo uptake, PKH67-labeled exosomes were applied to the dorsal skin of mice treated with IMQ for 4 days. After 24 h, skin tissues were collected, cryosectioned, and examined using a fluorescence microscope.

H&E staining, immunofluorescence (IF), and immunohistochemistry (IHC)

Skin tissues were fixed, paraffin-embedded, sectioned at 5 μm, deparaffinized, hydrated, and stained with hematoxylin and eosin. For IF, antigen retrieval and blocking were followed by overnight incubation with primary antibodies, then 2 h incubation with secondary antibodies, and DAPI nuclear counterstaining. For IHC, secondary antibody incubation was followed by chromogenic development, re-staining, dehydration, and mounting. For histological quantification, five non-overlapping fields per section were randomly selected. Epidermal thickness was measured using ImageJ software, inflammatory cell infiltration was quantified as the number of positive cells per field, and immunofluorescence signals were quantified as mean fluorescence intensity, and the percentage of positive cells was calculated relative to the total number of DAPI-positive nuclei within each field.

Primary antibodies used included: S100A8 (Proteintech #15792-1-AP, 1:100), IL-23 A (Proteintech #66196-1-Ig, 1:50), IL-17 A (Proteintech #26163-1-AP, 1:100), Ly6G (Invitrogen #14-5931-82, 1:100), GPX2 (ABclonal #A15999, 1:50), Cytokeratin-10 (Abcam #ab76318, 1:100), CD31 (Abcam #ab222783, 1:100), P65 (CST #8242, 1:100), Ki67 (CST #12202, 1:50), and IL-23R (ABclonal #A22561, 1:50). Secondary antibodies used included Alexa Fluor^® 488 Goat Anti-Rat IgG H&L (Abcam #ab150157, 1:200), CoraLite594 Goat Anti-Mouse IgG (Proteintech #SA00013-3, 1:200), CoraLite^® Plus 488 Goat Anti-Rabbit (Proteintech #RGAR002, 1:200), and CoraLite^® Plus 594 Goat Anti-Rabbit (Proteintech #RGAR004, 1:200).

Establishment of the IMQ-induced psoriasis mouse model

Eight-week-old BALB/c mice were obtained from the Guoke Ningbo Life Science and Health Industry Research Institute (Ningbo City, Zhejiang Province, China). To minimize suffering, animals were anesthetized with inhalation anesthesia using isoflurane (RWD #R510-22-10). After shaving their dorsal skin, 62.5 mg 5%- IMQ (Mingxin Pharmaceutical, Sichuan, China) was applied daily [27]. From day 4 onward, mice were anesthetized by inhalation, and DPSC-Exo (at a dose of 200 µg per mouse per day, suspended in PBS, determined the protein concentration of the isolated exosomes) or 0.1% tacrolimus ointment (Fuyuan Pharmaceutical, Beijing, China) was applied directly to the lesional skin [28]. After the applied agents had been absorbed and the skin surface was dry, the mice were returned to their cages. Imiquimod (IMQ) was administered two hours later. The dosage of DPSC-Exo was determined based on previously published studies and our preliminary experimental results. On the day 8, mice were sacrificed and lesional skin samples were collected via cervical dislocation. Therapeutic efficacy in the in vivo model was evaluated using the Psoriasis Area and Severity Index (PASI). Desquamation, thickening, and erythema were each scored on a scale of 0 to 4 (0 = none; 1 = mild; 2 = moderate; 3 = severe; 4 = very severe). The cumulative score (0–12) was used to indicate the severity of inflammation. To minimize observer bias, PASI scoring was performed independently by three researchers blinded to the experimental groups. All experimental procedures were approved by the Institutional Animal Ethics Committee and conducted in accordance with the GB/T35892-2018 guidelines and the ARRIVE guidelines 2.0.

Establishment of psoriasis models in vitro and ex vivo

Primary human keratinocytes were seeded at 1.8 × 10⁵ cells/well in 12-well plates. When they reached ~ 70% confluence, cells were stimulated with a cytokine cocktail (M5: TNF-α (novoprotein #C008), IL-22 (novoprotein #CH50), IL-1α (novoprotein #C070), IL-17 A (novoprotein #C774), OSM (acrobiosystems #H5213); each at 10 ng/mL) for 24–48 h to induce a psoriasis-like phenotype [29, 30].

Discarded human foreskin tissues were cut into 5 × 5 mm pieces [31], cultured in serum-free Williams’ E medium, and stimulated with M5 (10 ng/mL) cytokines to establish an ex vivo psoriasis model [32].

Quantitative real-time PCR (qRT-PCR)

Total RNA was extracted using Trizol, and cDNA was synthesized using an Evo M-MLV RT Kit (Accurate Biology #AG11707) or an All-in-one™ miRNA First-Strand cDNA Synthesis Kit (GeneCopoeia #AMRT-0020). qRT-PCR was performed with PerfectStart^® Green qPCR SuperMix (TransGen Biotech #AQ601). β-Actin and H36B4 were used as internal controls for mRNA; RNU6B was used for miRNA normalization. Relative expression levels were calculated using the 2^−ΔΔCt method. Primers used are listed in Supplementary Table 1.

Western blot analysis

Total, cytoplasmic, and nuclear proteins were extracted using RIPA buffer (with 1% protease and phosphatase inhibitors) or a nuclear/cytoplasmic extraction kit (Beyotime #P0028). Protein concentrations were determined using the BCA assay. Equal amounts of protein were separated on 12–15% SDS-PAGE gels, transferred to PVDF membranes, blocked with 5% non-fat milk, and then probed with primary antibodies overnight. After incubation with HRP-conjugated secondary antibodies (CST #7074; CST #7076, 1:1000), signals were visualized using enhanced chemiluminescence (Solarbio #SW2050). Optical density analysis was performed using ImageJ software (NIH, Bethesda, MD, USA). The gray values of the target protein bands were normalized to those of the corresponding internal reference proteins (GAPDH, β-actin, or Lamin B) to calculate the relative protein expression levels. Antibodies used included IL-23A (proteintech #66196-1-Ig, 1:500), IL-23R (ABclonal #A22561, 1:500), S100A8 (proteintech #15792-1-AP, 1:1000), S100A9 (proteintech #26992-1-AP, 1:1000), IL-17A (proteintech #26163-1-AP, 1:1000), P65 (CST #8242, 1:1000), p-P65 (CST #3033, 1:1000), Lamin B (CST #13435, 1:500), GPX2 (ABclonal #A15999, 1:500), p-IKKα/β (CST #2697, 1:500), and IKKα/β (Abways #CY5660, 1:500), Beta Actin Monoclonal antibody(proteintech #66009-1-Ig, 1:2000), Calnexin Polyclonal antibody (proteintech #10427-2-AP, 1:500), TSG101 Polyclonal antibody (proteintech #28283-1-AP,1:500), CD63 Rabbit mAb (ABclonal #A19023), Anti-CD81 antibody [M38](Abcam #ab79559,1:500), GAPDH (14C10) Rabbit mAb (CST #2118,1:1000).

Cell transfection experiments

To evaluate gene function, DPSCs or keratinocytes were transfected with specific miRNA mimics/inhibitors or siRNAs (Knock down gene expression: siGPX2, siP65) using Lipofectamine 3000 (Thermo Fisher Scientific, USA, #L000001). For 6-well plates, 12.5 µL miRNA mimic/inhibitor or siRNA was mixed with 125 µL Opti-MEM (solution A). In parallel, 7.5 µL Lipofectamine 3000 was mixed with 125 µL Opti-MEM (solution B). After 5 min, A and B were combined for 15 min, then added to cells. After 8 h, the medium was replaced and cells were cultured for 24 h before experiments. The oligo sequences of mimic/inhibitors and siRNAs used are listed in Supplementary Table 2.

For P65 overexpression (OE-P65), 3 µg plasmid and 5 µL P3000 in 125 µL Opti-MEM (solution A) were combined with 7.5 µL Lipofectamine 3000 in 125 µL Opti-MEM (solution B), incubated for 15 min, and added to cells. After 8 h, the medium was replaced, and cells were cultured for 72 h.

RNA sequencing

Primary keratinocytes were treated with M5 (10 ng/mL) alone or with M5 + DPSC-Exo (50 µg/mL) for 24 h. Total RNA was collected and sequenced by the Beijing Genomics Institute (BGI, Beijing, China). DEGs were defined as |log2FC| ≥ 1, q < 0.05. Volcano plots, heatmaps, and KEGG pathway analyses were generated. The data has been successfully uploaded to the National Genomics Data Center (NGDC) platform (No: HRA016705).

Statistical analysis

All experiments were performed in triplicate. Data are expressed as means ± standard deviation (SD). Statistical comparisons were performed using Student’s t-test (two groups) whereas one-way ANOVA followed by Bonferroni post hoc testing was used for multiple-group comparisons. Analyses were conducted with GraphPad Prism 9.5.0 (GraphPad Software, San Diego, California, USA). A P-value < 0.05 was considered statistically significant.

Results

DPSC-Exo can be purified and efficiently delivered to primary human keratinocytes and murine skin

We first isolated and authenticated DPSCs derived from human dental pulp tissues (representative images of pulp tissue and cultured DPSCs are shown in Fig. 1A). DPSCs exhibited osteogenic and adipogenic differentiation capacity (Fig. 1B), and flow cytometry confirmed their mesenchymal phenotype (CD44+, CD105+, CD90+) with minimal expression of hematopoietic/endothelial markers (CD45–, CD19–, CD14–), validating their identity as MSCs (Fig. 1C).

Fig. 1.

Isolation and characterization of DPSCs and DPSC-Exo, and their uptake in keratinocytes and skin. A Representative images of human dental pulp tissue and cultured DPSCs (scale bars: 25 μm). B Multipotency of DPSCs demonstrated by osteogenic (Alizarin Red) and adipogenic (Oil Red O) induction (scale bars: 25 μm). C Flow cytometry of DPSC surface markers showing the MSC phenotype (CD44, CD105, CD90 positive) and the lack of hematopoietic/endothelial markers (CD45, CD19, CD14 negative). D Schematic workflow for the isolation of DPSC-Exo. E TEM of DPSC-Exo showing typical cup-shaped vesicles (scale bars: 100 nm). F NTA (ZetaView) showing a 30–150 nm particle size distribution. G Western blot confirming the expression of exosomal markers (CD63, TSG101, CD81) and the absence of Calnexin. Full uncropped image is shown in Supplementary Fig. 1. H Uptake of PKH67-labeled DPSC-Exo by primary human keratinocytes after 24 h (with F-actin counterstain) (scale bars: 25 μm). I Penetration of PKH67-labeled DPSC-Exo into IMQ-treated murine dorsal skin (frozen sections) (scale bars: 25 μm)

Exosomes collected from DPSC-conditioned medium were isolated through a standardized workflow (Fig. 1D). Transmission electron microscopy (TEM) revealed the characteristic cup-shaped morphology of exosomes (Fig. 1E), while nanoparticle tracking analysis (NTA) confirmed a particle size distribution of 30–150 nm (Fig. 1F), and Western blotting demonstrated their expression of canonical exosomal markers CD63, TSG101, and CD81, with an absence of Calnexin (Fig. 1G). Together, these data establish a well-defined DPSC-Exo preparation for downstream mechanistic studies.

To assess their delivery, PKH67-labeled DPSC-Exo were co-cultured with primary human keratinocytes and were efficiently internalized within 24 h, as visualized using F-actin staining (Fig. 1H). In vivo, topically applied PKH67-labeled DPSC-Exo penetrated IMQ-treated murine dorsal skin and were detectable in deeper tissue layers (Fig. 1I).

DPSC-Exo alleviate IMQ-induced psoriatic lesions and suppress keratinocyte hyperproliferation, angiogenesis, and inflammatory cytokine expression in vivo

To evaluate the therapeutic effects of DPSC-Exo in vivo, we established an imiquimod (IMQ)-induced psoriasis-like mouse model (Fig. 2A). From day 4 of IMQ application, mice were treated with either PBS, DPSC-Exo, or 0.1% tacrolimus (positive control). Treatment with DPSC-Exo or tacrolimus markedly improved skin lesions, as reflected by reduced scaling and erythema (Fig. 2B) and lowered PASI scores compared with PBS-treated mice (Fig. 2C). Histological examination further showed that treatment with DPSC-Exo decreased the epidermal and total skin thickness that was increased by IMQ (Fig. 2D, E). In addition, IMQ induced marked angiogenesis in psoriatic lesions, which was inhibited by treatment with DPSC-Exo or tacrolimus, as evidenced by a reduction in vascular density (Fig. 2F, G).

Fig. 2.

DPSC-Exo alleviate psoriatic skin lesions in an IMQ-induced mouse model. A Schematic diagram of the animal experiment. B Representative images of dorsal skin from mice in different treatment groups on day 4 and day 8 (n = 3). C Severity scores of Erythema, Thickening, and Desquamation (PASI scale) in mice on day 8. D H&E staining of lesional skin sections (scale bars: 100 μm (upper), 50 μm (lower)). E Quantification of epidermal and total skin thickness of images shown in D. F Representative images of vascular density in lesional skin. G Quantification of vascular density. All experiments were repeated three times. Statistical analysis was performed using analysis of variance (ANOVA) followed by Bonferroni post hoc testing. P values are indicated as follows: *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001

To further characterize these effects, we analyzed keratinocyte proliferation, differentiation, immune infiltration, and inflammatory signaling in lesional skin. Quantitative PCR and Western blot analyses confirmed that treatment with DPSC-Exo decreased the mRNA levels of TNF-α, IL-6, IL-1β, IL-23A, S100A8, S100A9, and CXCL1(Fig. 3A), as well as the protein levels of IL-23R, IL-17A, S100A8, and S100A9 (Fig. 3B, C). Notably, the extent of cytokine inhibition by DPSC-Exo was comparable to that observed with 0.1% tacrolimus, and in some cases (e.g., IL-6, IL-1β, and IL-23 A) appeared even more pronounced. DPSC-Exo reduced the number of Ki67-positive proliferating basal keratinocytes and restored keratinocyte differentiation, as indicated by KRT-10 expression (Fig. 3D, Supplementary Fig. 2A). Neutrophil infiltration (Ly6G⁺ cells) and S100A8 expression were markedly reduced, and the expression of psoriasis-associated cytokines IL-23A, IL-23R, and IL-17A was significantly decreased in the DPSC-Exo–treated group (Fig. 3D, E, Supplementary Fig. 2A).

Fig. 3.

DPSC-Exo suppress keratinocyte hyperproliferation, neutrophil infiltration, and inflammatory cytokine expression in vivo. A Relative mRNA expression level of TNF-α, IL-6, IL-1β, IL-23A, S100A8, S100A9 and CXCL1 in skin lesions. B Western blot analysis of IL-23R, IL-17A, S100A8 and S100A9. Full uncropped image is shown in Supplementary Fig. 3. C Quantification of protein expression of Western blots shown in B. D IHC staining of Ki67 and IL-23R and IF staining of KRT-10 and S100A8 in lesional skin (day 8) (scale bars: 50 μm). E IF staining of IL-23A, Ly6G, IL-17A, and CD31 (scale bars: 50 μm). All experiments were repeated three times. Statistical analysis was performed using analysis of variance (ANOVA) followed by Bonferroni post hoc testing. P values are indicated as follows: *P < 0.05, **P < 0.01, ***P < 0.001

Collectively, these data demonstrate that DPSC-Exo effectively ameliorate psoriatic skin pathology by normalizing keratinocyte homeostasis, suppressing immune infiltration and angiogenesis, and downregulating the IL-23/IL-17 inflammatory axis—comparable to standard immunosuppressive therapy.

DPSC-Exo suppress pro-inflammatory cytokine expression in in vitro and ex vivo psoriasis models

Building on the in vivo findings (Figs. 2 and 3) that DPSC-Exo alleviate psoriatic pathology and reduce cytokine production, we next examined whether those effects could be recapitulated in controlled in vitro and ex vivo psoriasis models. Primary human keratinocytes, which play a central role in the initiation of psoriatic inflammation, were stimulated with the M5 cytokine cocktail (TNF-α, IL-22, IL-1α, IL-17A, and Oncostatin M (OSM)) to mimic the psoriatic microenvironment.

In keratinocytes treated with M5 alone, the expression of pro-inflammatory mediators was strongly induced at both the mRNA and protein levels. Co-treatment with DPSC-Exo significantly suppressed the mRNA expression of S100A8, S100A9, IL-1β, IL-1α, IL-6, IL-23A, and TNF-α compared with M5 alone (Fig. 4A). Protein levels of S100A9, S100A8, IL-23A, IL-23R and IL-17A were similarly reduced at 24 h (Fig. 4B, C) and remained suppressed after 48 h of exposure (Fig. 4D, E; Supplementary Fig. 2B).

Fig. 4.

DPSC-Exo inhibit the expression of inflammatory factors in in vitro and ex vivo psoriasis models. A Relative mRNA expression levels of IL-23A, S100A8, S100A9, IL-1β, IL-1α, IL-6, and TNF-α in primary human keratinocytes treated with M5 ± DPSC-Exo for 24 h. B Protein expression levels of S100A9, S100A8, IL-23A, IL-23R and IL-17A in keratinocytes treated for 24 h. Full uncropped image is shown in Supplementary Fig. 4. C Quantification of protein expression levels in B. D Protein expression levels of S100A9, S100A8, IL-23A, IL-23R and IL-17A in keratinocytes treated for 48 h. Full uncropped image is shown in Supplementary Fig. 5. E Quantification of protein expression levels in D. F mRNA expression levels of S100A8, S100A9, IL-1α, IL-17 A, IL-6, IL-1β and IL-23A in ex vivo M5-stimulated foreskin tissue treated with or without DPSC-Exo (50 µg/mL). All experiments were repeated three times. Statistical analysis was performed using ANOVA followed by Bonferroni post hoc testing. P values are indicated as follows: *P < 0.05, **P < 0.01, ***P < 0.001

To more closely model psoriatic progression in human skin, we established an ex vivo psoriasis model using M5-stimulated foreskin tissue (Supplementary Fig. 2C). Consistent with the keratinocyte experiments, treatment with DPSC-Exo significantly decreased the expression of S100A8, S100A9, IL-1α, IL-17A, IL-6, IL-1β and IL-23A in foreskin tissue samples (Fig. 4F).

Together with the in vivo results, these data demonstrate that DPSC-Exo exert robust anti-inflammatory effects across several different psoriasis models. By consistently suppressing the expression of key cytokines of the IL-23/IL-17 axis and psoriatic alarmins (S100A8/9), DPSC-Exo validate their translational potential as a cell-free therapy.

RNA-seq analysis identifies NF-κB signaling as a central target of DPSC-Exo in psoriatic keratinocytes

To elucidate the molecular mechanism(s) underlying the therapeutic effects of DPSC-Exo, we performed RNA-seq analysis on primary human keratinocytes treated for 24 h with M5 alone or with M5 plus DPSC-Exo. Differential expression analysis revealed 43 genes that were upregulated and 42 genes that were downregulated in the DPSC-Exo group (Fig. 5A). Heatmap analysis highlights the strongly expressed upregulated genes (e.g., PAI-1, MMP9, GPX2, ITGB6) and the downregulated genes (e.g., PLA2G4B, TGM3, IL-23 A, PTGS2) (Fig. 5B, C). qRT-PCR validation confirmed the accuracy of these RNA-seq findings (Fig. 5D).

Fig. 5.

DPSC-Exo inhibit the activation of NF-κB signaling in psoriasis models. A Volcano plot of DEGs in keratinocytes treated with M5 + DPSC-Exo or with M5-only (|log2FC| ≥ 1, q < 0.05). B, C Heatmaps of selected upregulated (B) and downregulated (C) DEGs with TPM ≥ 10. D qRT-PCR validation of four upregulated (PAI-1, MMP9, GPX2, ITGB6) and four downregulated (PLA2G4B, TGM3, IL-23A, PTGS2) genes. E KEGG pathway enrichment analysis of DEGs (|log2FC|≥ 1). F TRRUST enrichment analysis of DEGs using Metascape; NF-κB regulators ranked among the top terms. G, H Western blot of p65 and p-p65 in IMQ-induced mouse skin lesions G and ex vivo psoriasis model H. Full uncropped image is shown in Supplementary Fig. 7, 8. I Western blot of p65, p-p65, and IKKα/β phosphorylation in primary keratinocytes. Full uncropped image is shown in Supplementary Fig. 9. J Nuclear/cytoplasmic fractionation showing reduced nuclear p65 in DPSC-Exo–treated keratinocytes. Full uncropped image is shown in Supplementary Fig. 10. K Immunofluorescence images showing inhibition of p65 nuclear translocation in the M5 + DPSC-Exo group. All experiments were repeated three times. Statistical analysis was performed using a two-sided Student’s t-test for comparisons between two groups, and ANOVA followed by Bonferroni post hoc testing for multiple-group comparisons. P values are indicated as follows: *P < 0.05, **P < 0.01, ***P < 0.001

KEGG pathway enrichment analysis of differentially expressed genes (DEGs) revealed the significant involvement of multiple inflammation-related pathways, including TNF, NF-κB, MAPK, JAK-STAT, and PI3K–Akt, all of which are known to contribute to the pathogenesis of psoriasis (Fig. 5E). TRRUST enrichment analysis using Metascape further identified NF-κB–related transcriptional regulators (NF-κB1, RELA, NF-κBIA) among the top-ranked hits (Fig. 5F), suggesting that NF-κB signaling may represent a central node targeted by DPSC-Exo.

To validate that prediction, we assessed NF-κB activation across the different psoriasis models. In both the IMQ-induced psoriasis mouse model and the ex vivo foreskin model, DPSC-Exo treatment markedly suppressed the phosphorylation of p65 compared with the controls (Fig. 5G, H). In the in vitro keratinocyte model, DPSC-Exo significantly inhibited the phosphorylation of both p65 and its upstream activator IKKα/β (Fig. 5I). Furthermore, treatment with DPSC-Exo reduced the nuclear accumulation of p65, as shown by Western blotting of nuclear/cytoplasmic fractions (Fig. 5J) and confirmed by fluorescence imaging (Fig. 5K), both of which were statistically significant differences (Supplementary Fig. 6A-D).

Collectively, these data indicate that DPSC-Exo broadly reprogram psoriatic keratinocytes at the transcription level and exert their anti-inflammatory activity, likely by inhibiting NF-κB pathway activation.

DPSC-Exo exert anti-inflammatory effects through the inhibition of NF-κB signaling

Having established that DPSC-Exo suppress NF-κB signaling, we next tested whether the modulation of p65 activity could alter the anti-inflammatory effects of exosomes. We successfully overexpressed p65 (OE-P65) in primary human keratinocytes and found that the intracellular overexpression of P65 significantly promoted the expression of pro-inflammatory factors (S100A8, S100A9, IL-1α, IL-23A, IL-1β, IL-8, IL-6)(Supplementary Fig. 6E-G). The overexpression of p65 (OE-P65) in primary human keratinocytes abolished the protective effects of DPSC-Exo; compared with the M5 + Exo group, the M5 + Exo + OE-P65 group exhibited significantly increased mRNA expression levels of S100A8, S100A9, IL-1α, IL-1β, IL-6, and IL-23A (Fig. 6A), as well as elevated protein levels of IL-17A, S100A8, S100A9, IL-23R, and IL-23A (Fig. 6B, Supplementary Fig. 6I).

Fig. 6.

DPSC-Exo exert anti-inflammatory effects through the inhibition of NF-κB signaling. A Relative mRNA expression levels of S100A8, S100A9, IL-1α, IL-1β, IL-6, and IL-23A in primary human keratinocytes treated with M5, M5 + DPSC-Exo, or M5 + DPSC-Exo + OE-p65. B Protein expression levels of IL-17A, S100A8, S100A9, IL-23R, and IL-23A under the same conditions as in A. Full uncropped image is shown in Supplementary Fig. 11. C Relative mRNA expression levels of S100A8, S100A9, IL-8, IL-23A, IL-1α, IL-1β, IL-6 and CCL20 in keratinocytes treated with M5, M5 + si-NC, or M5 + si-p65. D Protein expression levels of p65, IL-17A, S100A8, S100A9, IL-23R, and IL-23A in keratinocytes under the same conditions as in C. Full uncropped image is shown in Supplementary Fig. 12. All experiments were repeated three times. Statistical analysis was performed using ANOVA followed by Bonferroni post hoc testing for multiple-group comparisons. P values are indicated as follows: **P < 0.01, ***P < 0.001

Conversely, the knockdown of p65 expression mimicked the therapeutic effects of DPSC-Exo. In the p65 knockdown group, mRNA levels of S100A8, S100A9, IL-8, IL-23A, IL-1α, IL-1β, IL-6 and CCL20 were markedly reduced compared with M5 stimulation alone (Fig. 6C). Consistently, protein levels of IL-17A, S100A8, S100A9, IL-23R and IL-23A were also decreased, and total p65 protein levels were diminished (Fig. 6D), all of which were statistically significantly differences (Supplementary Fig. 6H, J).

Together, these results demonstrate that the anti-inflammatory effects of DPSC-Exo depend on their ability to suppress NF-κB signaling.

DPSC-Exo exert anti-inflammatory effects through the GPX2–NF-κB signaling pathway

To further define the mechanism by which DPSC-Exo regulate NF-κB signaling, we revisited the RNA-seq dataset (Fig. 5B) and noted that GPX2 was one of the most strongly upregulated genes after DPSC-Exo treatment. GPX2 has been reported to negatively regulate NF-κB activity [22, 23], which suggests that it might represent a novel mediator of exosome action. We therefore investigated the role of GPX2 in our psoriasis models.

In IMQ-induced mouse psoriasis lesions, treatment with DPSC-Exo markedly restored GPX2 expression, which was otherwise suppressed in the IMQ + PBS group, as shown by immunofluorescence staining (Fig. 7A, B). Consistent results were obtained in the ex vivo foreskin model (Fig. 7C) and in M5-stimulated keratinocytes (Fig. 7D), where DPSC-Exo treatment significantly upregulated GPX2 protein expression, all of which were statistically significantly differences (Supplementary Fig. 13A, C).

Fig. 7.

DPSC-Exo exert anti-inflammatory effects through the GPX2–NF-κB signaling pathway. A Immunofluorescence staining of GPX2 in IMQ-induced psoriatic lesions of mice treated with PBS, DPSC-Exo (scale bars: 50 μm). B Quantification of GPX2 staining intensity in A. C, D Western blot analysis of GPX2 protein expression in the ex vivo psoriasis model C and in M5-stimulated keratinocytes D treated with or without DPSC-Exo. Full uncropped image is shown in Supplementary Fig. 14, 15. E Western blot analysis of GPX2, p-P65, total p65, S100A8, S100A9, IL-23R, IL-23A, IL-17A in keratinocytes transfected with si-NC, si-GPX2, or si-GPX2 + DPSC-Exo, Full uncropped image is shown in Supplementary Fig. 16. F Relative mRNA expression levels of GPX2, S100A8, S100A9, IL-23A, IL-8, IL-6, IL-1β and IL-1α in keratinocytes under the same conditions as E. All experiments were repeated three times; Statistical analysis was performed using ANOVA followed by Bonferroni post hoc testing for multiple-group comparisons. P values are indicated as follows: *P < 0.05, **P < 0.01, ***P < 0.001

To test whether GPX2 is required for the anti-inflammatory effects of DPSC-Exo, we performed GPX2 knockdown in keratinocytes. Compared with controls, knockdown of GPX2 in the siGPX2 group was confirmed at both mRNA and protein levels, siGPX2 significantly increased both mRNA levels of S100A8, S100A9, IL-23A, IL-8, IL-6, IL-1β and IL-1α, and protein levels of p-P65, S100A8, S100A9, IL-23R, IL-23A, IL-17A (Fig. 7E, F),all of which were statistically significantly differences (Supplementary Fig. 13B). Notably, when keratinocytes with GPX2 knockdown were treated with DPSC-Exo (siGPX2 + Exo group), this inflammatory phenotype was only minimally rescued, which indicates that GPX2 is essential for mediating the inhibitory effects of DPSC-Exo on NF-κB signaling.

Together, these findings identify GPX2 as a novel and necessary mediator of the therapeutic activity of DPSC-Exo. By restoring GPX2 expression, DPSC-Exo suppress NF-κB signaling and downstream inflammatory cytokine production, thereby alleviating psoriatic inflammation.

DPSC-Exo exert anti-inflammatory effects by delivering miR-1246 and miR-17-3p to regulate the GPX2–NF-κB pathway

Given that exosomal miRNAs often serve as essential mediators of intercellular communication, we next investigated whether specific DPSC-Exo miRNAs regulate GPX2 expression. Using miRNA target prediction platforms (miRWalk and TarBase), we identified a set of candidate miRNAs predicted to bind GPX2, with overlapping predictions shown in Fig. 8A. A review of the literature further supported two candidates: miR-17-3p, known for its anti-inflammatory activity and the regulation of NF-κB signaling [33, 34], and miR-1246, one of the most highly expressed miRNAs in DPSC-Exo, has been reported to exert immunomodulatory effects and to upregulate the expression of antioxidant enzymes such as SOD1, SOD2, and CAT, thereby contributing to the regulation of redox balance [35–38]. TargetScan analysis additionally predicted a potential binding site between miR-17-3p and GPX2.

Fig. 8.

DPSC-Exo exert anti-inflammatory effects by delivering miR-1246 and miR-17-3p. A Schematic diagram of candidate miRNAs predicted to target GPX2 by miRWalk and TarBase. B, C Protein expression levels of GPX2, total p65, and p-p65 in keratinocytes treated with M5, miRNA mimics (miR-1246 or miR-17-3p), or controls. Full uncropped image is shown in Supplementary Fig. 18, 19. D, F Protein expression levels of IL-23A, IL-23R, S100A8, and S100A9 in keratinocytes treated as in B, C, Full uncropped image is shown in Supplementary Fig. 20, 21. E, G mRNA expression levels of IL-23A, IL-6, IL-1β, IL-8, S100A9 and S100A8 in keratinocytes treated with DPSC-Exo, Exo-inhibitor-miR-1246, or Exo-inhibitor-miR-17-3p. All experiments were repeated three times. Statistical analysis was performed using ANOVA followed by Bonferroni post hoc testing for multiple-group comparisons. P values are indicated as follows: *P < 0.05, **P < 0.01, ***P < 0.001

qRT-PCR analysis confirmed the presence of both miR-1246 and miR-17-3p in DPSC-Exo (Supplementary Fig. 17A). Functional experiments demonstrated that the overexpression of miR-1246 or miR-17-3p (mimics) in keratinocytes rescued the M5-induced downregulation of GPX2 and suppressed p65 phosphorylation (Fig. 8B, C; Supplementary Fig. 17D-E). Moreover, the overexpression of either miRNA significantly reduced the M5-induced increase in IL-23A, IL-23R, S100A8, and S100A9 protein expression (Fig. 8D, F), with the differences reaching statistical significance (Supplementary Fig. 17F-G). At the same time, either of the two tested miRNAs reduced the M5-induced increase in the mRNA expression of pro-inflammatory factors (IL-1α, IL-1β, IL-6, IL-8, IL-23A, S100A8, S100A9) and rescued the M5-induced downregulation of GPX2 mRNA levels (Supplementary Fig. 17H, I).

Conversely, the inhibition of miR-1246 or miR-17-3p within DPSC-Exo (Exo-inhibitor-miR-1246, Exo-inhibitor-miR-17-3p) markedly reduced their therapeutic efficacy. Compared with control Exo, exosomes lacking either miRNA failed to suppress the expression of proinflammatory cytokines, as reflected by the significantly increased mRNA levels of IL-23A, IL-6, IL-1β, IL-8, S100A9 and S100A8 in keratinocytes (Fig. 8E, G; Supplementary Fig. 17C).

These results indicate that miR-1246 and miR-17-3p are key exosomal cargos that mediate the anti-inflammatory effects of DPSC-Exo by restoring GPX2 expression and inhibiting NF-κB activation.

Discussion

The results of this study demonstrate that treatment with DPSC-Exo effectively alleviate psoriatic pathology through a novel miR-1246/miR-17-3p–GPX2–NF-κB axis. In vivo, ex vivo, and in vitro models demonstrated that treatment with DPSC-Exo markedly reduced keratinocyte hyperproliferation, neutrophil infiltration, angiogenesis, and the expression of psoriasis-associated cytokines. Notably, pro-inflammatory mediators such as IL-23A, IL-6, S100A8, and S100A9 were strongly suppressed, highlighting the ability of DPSC-Exo to downregulate both cytokine signaling and antimicrobial peptide production. The reduction in vascular proliferation, a hallmark of inflamed psoriatic skin, further confirmed the broad anti-inflammatory and tissue-stabilizing properties of these exosomes. Together, these findings establish DPSC-Exo as an effective acellular therapy capable of simultaneously modulating immune and epithelial compartments in chronic skin inflammation.

Keratinocytes are increasingly recognized as active initiators of psoriasis, amplifying immune cascades through cytokine release and abnormal differentiation [39, 40]. Our demonstration that DPSC-Exo normalize keratinocyte function in both in vitro (M5-stimulated keratinocytes) and ex vivo (foreskin explants) models add mechanistic depth to the in vivo findings. These parallel results underscore the translational relevance of DPSC-Exo and support their potential as a clinically applicable, cell-free therapy for psoriasis. Because keratinocytes share conserved inflammatory signaling pathways with epithelia of the oral mucosa, gut, and airway, this mechanism may extend beyond psoriasis to other epithelial inflammatory diseases.

Mechanistically, transcriptomic analysis and functional validation converged on NF-κB signaling as the central target of DPSC-Exo. The inhibition of p65 and IKKα/β phosphorylation, the blockade of p65 nuclear translocation, and the suppression of downstream cytokine genes confirm that NF-κB activity is curtailed. Importantly, gain- and loss-of-function studies demonstrated that p65 overexpression reversed, while p65 knockdown mimicked, the anti-inflammatory effects of DPSC-Exo, establishing NF-κB inhibition as an essential mechanism of action. Although TRRUST enrichment also identified STAT1 and STAT3 among the top-ranked transcriptional regulators, our functional assays clearly indicate that NF-κB is the dominant signaling pathway modulated by DPSC-Exo. This mechanistic precision provides a framework for future translational efforts to target epithelial NF-κB activation using cell-free vesicle-based strategies.

A particularly novel aspect of this study is the identification of GPX2 as a critical mediator. GPX2 is an epithelial antioxidant enzyme that detoxifies hydrogen peroxide and organic hydroperoxides, thereby limiting the accumulation [41–43]. Because inflammation and oxidative stress form a vicious cycle in psoriasis [44], restoring GPX2 function interrupts this loop. Our data show that DPSC-Exo robustly upregulate GPX2 expression, and that GPX2 knockdown abolishes their ability to inhibit NF-κB and cytokine expression. This finding introduces GPX2 as a previously unrecognized regulator of psoriatic inflammation and as a new molecular target of exosome-based therapy. By linking redox control to inflammatory resolution, our study highlights a broader biological principle: stem cell–derived exosomes restore epithelial homeostasis by rebalancing oxidative and inflammatory signaling.

We further demonstrated that miR-1246 and miR-17-3p are dominant DPSC-Exo cargos involved in GPX2 regulation. Both miR-1246 and miR-17-3p have been reported to exert anti-inflammatory and pro-regenerative effects in multiple experimental settings. miR-1246 is a microRNA highly conserved among mammals, including humans. Although a homologous sequence has not yet been clearly identified in mice, it is the most abundantly expressed microRNA in human DPSC-Exo and plays an important role in restoring oxidative stress balance and modulating immune cell function [35]. Mechanistically, miR-1246 promotes the transcriptional expression of antioxidant enzymes through the SKP2/P62/Keap1–Nrf2 signaling axis [38]. In addition, it reduces the expression of pro-inflammatory cytokines, enhances macrophage autophagy, and promotes M2 macrophage polarization [45, 46]. Through these actions, miR-1246 suppresses excessive immune activation and contributes to tissue repair and remodeling. miR-17-3p is highly conserved during evolution and shows strong sequence homology between humans and mice. Increasing evidence indicates that this microRNA plays an important immunomodulatory role in the inflammatory microenvironment of multiple tissues. For example, miR-17-3p inhibits the NF-κB–mediated endothelial inflammatory response by targeting NIK and IKKβ-binding proteins [33]. In addition, it promotes macrophage apoptosis, thereby facilitating the resolution of inflammation and the restoration of tissue homeostasis [47]. We further predicted potential binding sites between miR-17-3p and the 3′UTR of GPX2 through bioinformatics analysis. Although miRNAs are generally thought to bind the 3′UTR in the cytoplasm and repress gene expression, increasing evidence indicates that, under specific cellular contexts, miRNAs can instead enhance target gene translation or stabilize mRNAs via non-canonical mechanisms following 3′UTR binding [48]. Moreover, certain miRNAs are capable of translocating into the nucleus and directly activating gene transcription through complementary interactions with promoter regions. For example, miR-17-5p has been shown to bind the KPNA2 promoter, leading to a significant increase in KPNA2 mRNA and protein expression [49]. Notably, miR-17-5p and miR-17-3p are generated from opposite arms of the same precursor (pre-miR-17). The demonstrated nuclear function of miR-17-5p raises the possibility that miR-17-3p may possess similar capacities for nuclear entry and transcriptional regulation. Based on the anti-inflammatory and tissue-repair effects of DPSC-Exo observed in this study, we propose that miR-17-3p and miR-1246 enriched in DPSC-Exo are key contributors to these therapeutic effects. To our knowledge, however, neither miRNA has previously been linked to psoriasis or GPX2 regulation. In the present study, both miRNAs restored GPX2 expression, inhibited NF-κB activation, and reduced pro-inflammatory cytokine production under inflammatory conditions. Conversely, inhibition of these miRNAs in exosomes attenuated the therapeutic effects of DPSC-Exo, supporting their functional contribution.

These findings indicate that exosomal miRNAs can function as transferable regulatory signals capable of modulating epithelial stress responses, and suggest potential strategies for engineering exosome cargos for disease-specific therapeutic applications. Nevertheless, we cannot exclude the possibility that other exosomal miRNAs or cargos may also contribute to these effects, which should be investigated in future studies.

Taken together, this study provides mechanistic insight and preclinical evidence supporting the therapeutic potential of DPSC-Exo in psoriasis. By demonstrating consistent effects across in vivo, ex vivo, and in vitro models, and by implicating a miRNA–GPX2–NF-κB axis, our findings support the concept of exosome-based intervention in inflammatory skin disease. From a translational perspective, DPSC-Exo may be adaptable to topical or microneedle-based delivery strategies and offer a potentially scalable, low-immunogenic alternative to current immunosuppressive approaches. In addition, their accessibility from dental tissue may facilitate cost-effective production.

Several limitations should be acknowledged. First, the therapeutic effects were evaluated in an IMQ-induced mouse model, ex vivo human skin explants, and primary keratinocyte systems, which do not fully capture the complexity of human psoriasis. Second, although our data support a role for the miR-1246/miR-17-3p–GPX2–NF-κB axis, the precise molecular mechanism by which these miRNAs regulate GPX2 expression was not directly determined. Third, exosomes derived from different donors were prepared under standardized conditions and showed consistent effects in our experiments; however, donor-to-donor variability remains an important consideration for future studies. Finally, long-term efficacy, safety, and delivery optimization were not addressed in the present work.

In conclusion, DPSC-Exo represent a promising preclinical acellular therapeutic candidate for psoriasis, acting at least in part through delivery of miR-1246 and miR-17-3p to modulate GPX2 expression and suppress NF-κB–driven inflammation. More broadly, these findings support the potential of stem cell–derived exosomes to restore epithelial redox–inflammatory balance. However, whether miR-1246 and miR-17-3p regulate GPX2 through 3′UTR binding, mRNA stabilization, or transcriptional mechanisms remains to be determined.

Conclusions

Stem cell exosomes rebalance epithelial oxidative–inflammatory signaling through a miR-1246/miR-17-3p–GPX2–NF-κB axis. Using psoriasis as a disease model, our study provides proof-of-concept that DPSC-Exo constitute a potentially translatable, acellular strategy for treating epithelial inflammatory disorders.

Electronic Supplementary Material

Below is the link to the electronic supplementary material.

Abbreviations

DPSC

Dental pulp stem cells

GPX2

Glutathione peroxidase 2

TEM

Transmission electron microscopy

NF-κB

Nuclear factor kappa-B

IMQ

Imiquimod

Author contributions

WS. drafted the manuscript, Experimental operation, collected the data and conducted the statistical analyses. ZD. Data analysis and processing. XQ. Participate in animal experiments and flow cytometry. HD. Isolation and culture of primary human pulp stem cells. FT. and SL. Isolation and culture of primary human keratinocytes. SY. KEGG PATHWAY enrichment analysis. GJ. Project control and adjustment. WX. contributed to the conception, experiment design, interpretation of data, and manuscript editing. YG. contributed to experiment design and interpretation of data, supervision. All authors approved the submitted version and agreed to be responsible for this work.

Funding

The work was supported by the National Natural Science Foundation of China (82273554).

Data availability

All data are available in the main text or the supplementary materials.

Declarations

Ethics approval and consent to participate

Primary human dental pulp stem cells were obtained from dental pulp tissues of extracted teeth that were discarded following impacted tooth removal surgery. Primary human keratinocytes were isolated from discarded foreskin tissue obtained after circumcision, with no personal identifying information collected. The study protocol was reviewed and approved by Ningbo Stomatology Hospital and its Ethics Committee (Approval No. NBKQYY2024LS-034; October 15, 2024). The approved project was entitled “Therapeutic Effects and Molecular Mechanisms of Exosomes Derived from Dental Pulp Stem Cells in Psoriasis.” Written informed consent was obtained from all participants for participation in the study and for the use of their samples, in accordance with applicable ethical and legal regulations. All animal experiments were approved by the Institutional Ethics Committee of the Guoke Ningbo Life Science and Health Industry Research Institute (Approval No. GK-2024-XM-1027; September 4, 2024), under the project entitled “Therapeutic Effects and Molecular Mechanisms of Exosomes Derived from Dental Pulp Stem Cells in Psoriasis.”

Consent for publication

All authors agreed with the publisher to publish this work.

Competing interests

The authors declare no competing interests.