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Cited by 4Advancements in Transdermal Drug DeliveryAcne and Rosacea Treatments and EffectsSilk-based biomaterials and applications

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Dissolvable silk microneedles delivering minocycline-loaded ZIF-8 nanoparticles for targeted modulation of sebocyte metabolism and improved acne therapy

Open access
Yang, Xuefan, Ruan, Dandan, Ye, Feng, Qiu, Xinlan, Li, Sitong, Huang, Lei, Zouboulis, Christos C, Mo, Xiaohui, Jiang, Xiping, Ju, Qiang·2026·Journal of Nanobiotechnology
DOI 10.1186/s12951-026-04221-8PMC PMC13088723
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Abstract

BACKGROUND: Acne Vulgaris (AV) lesions exhibit an acidic, sebum-rich, and inflammation-prone microenvironment in which conventional minocycline therapy is constrained by the stratum-corneum barrier and systemic exposure. Here, we present the fabrication and application of dissolvable silk fibroin microneedles encapsulating minocycline-loaded zeolitic imidazolate frameworks (Mino@ZIF-8/SF MNs) to achieve sebaceous gland-targeted, pH-responsive delivery and multimodal therapy. RESULTS: The Mino@ZIF-8/SF MNs display uniform conical morphology, excellent mechanical robustness (peak failure force ≈ 0.4 N per needle), rapid dissolution (< 1 min), high drug loading (≈ 40.11%) and encapsulation efficiency (≈ 70.2%), and negligible hemolytic activity. Under mildly acidic conditions (pH 5.5), minocycline release was markedly accelerated compared to physiological pH 7.4, reflecting the acidified acne microenvironment. Functionally, Mino@ZIF-8/SF MNs achieved > 95% inhibition of Cutibacterium acnes at 30 µg/patch and substantially attenuated sebocyte inflammatory responses. In heat-killed C. acnes-stimulated SZ95 sebocytes, the Mino@ZIF-8/SF MNs downregulated NFKB1, IL-1α, IL-1β, IL-6, IL-8 and MMP9 expression, along with suppression of cytokine-cytokine receptor interaction, IL-17 and NET-associated signaling pathways. RNA-sequencing also suggested that sebocyte metabolism may undergo reprogramming involving enhanced apoptosis, maintenance of mitochondrial oxidative activity, and modulation of PPARγ-related lipid metabolism, which could collectively contribute to reduced lipid droplet accumulation. In a C. acnes-induced acne-like mouse model, Mino@ZIF-8/SF MNs markedly accelerated lesion resolution, reduced lesion elevation, eschar formation, and diameter scores, normalized epidermal thickness, and decreased sebaceous lipid accumulation, while exhibiting no detectable systemic toxicity as confirmed by histology, hematology, and serum biochemistry. CONCLUSION: Collectively, this study establishes a nanobiotechnology platform that integrates metal-organic frameworks(MOF)-based pH-responsive delivery with antibacterial, anti-inflammatory, and metabolic reprogramming activities, offering a precise and minimally invasive multimodal strategy for sebaceous gland-targeted acne therapy.

Overview

CoChat Summary

TL;DR

Mino@ZIF-8/SF microneedles combine pH-responsive ZIF-8 nanoparticles with dissolvable silk fibroin to deliver minocycline into acne lesions, showing antibacterial, anti-inflammatory, and sebocyte metabolic effects. In a *C. acnes*-induced mouse model, the platform accelerated lesion resolution and reduced sebaceous lipid accumulation without detectable systemic toxicity.

Key findings

  • Mino@ZIF-8/SF MNs showed uniform conical needles (~600 μm height, 250 μm base diameter), peak failure force ≈0.4 N per needle, dissolution <1 min, drug loading ≈40.11%, encapsulation efficiency ≈70.2%, and hemolysis <1%.
  • Release was pH-responsive: >50% minocycline released at pH 5.5 within 12 h versus <20% at pH 7.4; antibacterial inhibition exceeded 95% for *C. acnes* at 30 µg/patch and was broad-spectrum against *E. coli* and *S. aureus*.
  • In heat-killed *C. acnes*-stimulated SZ95 sebocytes, treatment downregulated NFKB1, IL-1α, IL-1β, IL-6, IL-8, and MMP9, and suppressed cytokine-cytokine receptor interaction, IL-17, and NET-associated signaling; RNA-seq suggested apoptosis, oxidative phosphorylation, and PPARγ-related lipid metabolism changes.
  • In the mouse acne-like model, Mino@ZIF-8/SF MNs reduced elevation, eschar, and diameter scores, normalized epidermal thickness, decreased BODIPY and Oil Red O lipid signals, and showed no systemic toxicity by histology, hematology, or serum biochemistry.

Methods

  • ZIF-8 and Mino@ZIF-8 nanoparticles were synthesized by co-precipitation and characterized by TEM/SEM, XRD, FTIR, and UV-Vis; release was tested at pH 5.5 and 7.4. MNs were fabricated from 12% silk fibroin with Mino@ZIF-8 and a PVA backing via vacuum-assisted PDMS molding, then assessed for morphology, mechanical strength, dissolution, HPLC stability, cytocompatibility, and hemolysis.
  • In vitro antibacterial assays used *C. acnes*, *E. coli*, and *S. aureus* with colony counting and SEM. SZ95 sebocytes stimulated with heat-killed *C. acnes* were used for RNA-seq, KEGG analysis, and qPCR of inflammatory genes; scratch assays used HaCaT and HSF cells.
  • In vivo, female ICR mice received artificial sebum and intradermal *C. acnes*; five groups (n=6/group) received Model, SF MN, ZIF-8 MN, topical minocycline, or Mino@ZIF-8/SF MN on days 0, 2, and 4. Lesions were scored by Leeds revised acne grading; skin was analyzed by H&E, BODIPY, and Oil Red O, with systemic toxicity assessed by organ histology and blood/serum parameters.

Limitations

  • The paper states that mechanistic validation is required and that future work should directly compare the platform with clinically approved minocycline gels or foams; the present study focused on mechanistic evaluation rather than benchmarking commercial formulations.
  • The text makes evident that efficacy was tested only in a short-term (7-day) mouse model using artificial sebum plus intradermal *C. acnes*, with small group sizes (n=6/group; some analyses n=3–5), so long-term outcomes, resistance development, and human clinical translation remain unestablished.
  • The paper notes that in the plate-based antibacterial assay, microneedle performance may appear slightly weaker than free nanoparticles due to diffusion/exposure geometry rather than intrinsic activity.

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Registry

Crossref · 10.1186/s12951-026-04221-8

Cites

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Figures

Fig. 1 Characterization of Mino@ZIF-8 NPs. (A) TEM and SEM images of ZIF-8. (B) TEM and SEM images of Mino@ZIF-8. (C) Particle size distribution of ZIF-8 and Mino@ZIF-8. (D) XRD spectra of ZIF-8 and Mino@ZIF-8. (E) FTIR spectra of ZIF-8 and Mino@ZIF-8. (F) Standard calibration curve of minocycline at 382 nm. (G) In vitro cumulative release of minocycline from Mino@ZIF-8 under different pH conditions (pH 5.5 and pH 7.4)
Fig. 1 Characterization of Mino@ZIF-8 NPs. (A) TEM and SEM images of ZIF-8. (B) TEM and SEM images of Mino@ZIF-8. (C) Particle size distribution of ZIF-8 and Mino@ZIF-8. (D) XRD spectra of ZIF-8 and Mino@ZIF-8. (E) FTIR spectra of ZIF-8 and Mino@ZIF-8. (F) Standard calibration curve of minocycline at 382 nm. (G) In vitro cumulative release of minocycline from Mino@ZIF-8 under different pH conditions (pH 5.5 and pH 7.4)CC BY-NC-ND · PubMed Central
Fig. 2 Biocompatibility evaluation of Mino@ZIF-8 nanoparticles. (A) Live/dead staining of HaCaT and THP-1 cells treated with increasing concentrations of Mino@ZIF-8 (0–50 µg/mL) for 24 h. Green: live cells (Calcein-AM). Red: dead cells (PI). Scale bar = 50 μm. (B) 24 h cell viability and live/dead quantification of HaCaT cells assessed by CCK-8 assay and fluorescence image analysis. (C) Cell viability and live/dead quantification of THP-1 cells assessed by CCK-8 assay and fluorescence image analysis. (D) Hemolysis assay of red blood cells incubated with PBS, H₂O, free minocycline, ZIF-8, and Mino@ZIF-8. Hemolysis rates were calculated based on the absorbance of released hemoglobin. Data in Fig. 2B-D are presented as mean ± SD, n = 3 for each group; **p < 0.01, ***p < 0.001, ****p < 0.0001
Fig. 2 Biocompatibility evaluation of Mino@ZIF-8 nanoparticles. (A) Live/dead staining of HaCaT and THP-1 cells treated with increasing concentrations of Mino@ZIF-8 (0–50 µg/mL) for 24 h. Green: live cells (Calcein-AM). Red: dead cells (PI). Scale bar = 50 μm. (B) 24 h cell viability and live/dead quantification of HaCaT cells assessed by CCK-8 assay and fluorescence image analysis. (C) Cell viability and live/dead quantification of THP-1 cells assessed by CCK-8 assay and fluorescence image analysis. (D) Hemolysis assay of red blood cells incubated with PBS, H₂O, free minocycline, ZIF-8, and Mino@ZIF-8. Hemolysis rates were calculated based on the absorbance of released hemoglobin. Data in Fig. 2B-D are presented as mean ± SD, n = 3 for each group; **p < 0.01, ***p < 0.001, ****p < 0.0001CC BY-NC-ND · PubMed Central
Fig. 3 Fabrication and characterization of Mino@ZIF-8 SF microneedles (MNs). (A) SEM images showing the overall morphology and enlarged view of the microneedle array. (B) Time-dependent dissolution behavior of MNs in mouse skin observed at different time intervals (0–40 s). (C) Mechanical strength analysis of Mino@ZIF-8 SF MNs and SF MNs, as assessed by a texture analyzer. (D) HPLC chromatograms of free minocycline, Mino@ZIF-8 nanoparticles, and Mino@ZIF-8/SF microneedles. (E) Representative images of mouse dorsal skin before and at different time intervals (0–30 min) after MN application. (F) Schematic illustration of the fabrication process of Mino@ZIF-8 SF MNs using a vacuum-assisted layer-by-layer casting strategy
Fig. 3 Fabrication and characterization of Mino@ZIF-8 SF microneedles (MNs). (A) SEM images showing the overall morphology and enlarged view of the microneedle array. (B) Time-dependent dissolution behavior of MNs in mouse skin observed at different time intervals (0–40 s). (C) Mechanical strength analysis of Mino@ZIF-8 SF MNs and SF MNs, as assessed by a texture analyzer. (D) HPLC chromatograms of free minocycline, Mino@ZIF-8 nanoparticles, and Mino@ZIF-8/SF microneedles. (E) Representative images of mouse dorsal skin before and at different time intervals (0–30 min) after MN application. (F) Schematic illustration of the fabrication process of Mino@ZIF-8 SF MNs using a vacuum-assisted layer-by-layer casting strategyCC BY-NC-ND · PubMed Central
Fig. 4 In vitro antibacterial activity of Mino@ZIF-8/SF MNs. (A) Colony formation of C. acnes, E. coli, and S. aureus after treatment with MNs containing different Mino@ZIF-8 loadings (0–50 µg/patch). (B) Antibacterial comparison among free minocycline (Mino), ZIF-8, and Mino@ZIF-8 nanoparticles at equivalent drug concentrations. (C) Schematic illustration of the antibacterial assay workflow. (D) Quantitative antibacterial rates for different Mino@ZIF-8 concentrations. (E) Antibacterial rates of different treatment groups in B. (F) SEM images showing morphological changes in bacteria before and after Mino@ZIF-8 treatment. Severe structural disruption, membrane collapse, and surface porosity were observed in all tested strains after exposure. Scale bar: 1 μm. Data in Fig. 4D and E are presented as mean ± SD, n = 3 for each group
Fig. 4 In vitro antibacterial activity of Mino@ZIF-8/SF MNs. (A) Colony formation of C. acnes, E. coli, and S. aureus after treatment with MNs containing different Mino@ZIF-8 loadings (0–50 µg/patch). (B) Antibacterial comparison among free minocycline (Mino), ZIF-8, and Mino@ZIF-8 nanoparticles at equivalent drug concentrations. (C) Schematic illustration of the antibacterial assay workflow. (D) Quantitative antibacterial rates for different Mino@ZIF-8 concentrations. (E) Antibacterial rates of different treatment groups in B. (F) SEM images showing morphological changes in bacteria before and after Mino@ZIF-8 treatment. Severe structural disruption, membrane collapse, and surface porosity were observed in all tested strains after exposure. Scale bar: 1 μm. Data in Fig. 4D and E are presented as mean ± SD, n = 3 for each groupCC BY-NC-ND · PubMed Central
Fig. 5 Mino@ZIF-8/SF microneedles attenuate C. acnes-induced transcriptional activation and inflammatory signaling in SZ95 sebocytes. (A) RNA-seq heatmap showing HKC-induced upregulation of representative inflammatory genes and their suppression by Mino@ZIF-8/SF MNs. (B) KEGG enrichment analysis showing red-labeled core inflammatory pathways relevant to acne that were attenuated by MN treatment, and green-labeled regulatory or metabolic pathways representing potential targets for future therapeutic intervention. (C) qPCR quantification of NFKB1 expression across groups, showing HKC-induced transcriptional upregulation partially normalized by Mino@ZIF-8/SF MN extracts. (D) qPCR validation of IL-1α, IL-1β, IL-6, IL-8, and MMP9 in different treatment groups, with Mino@ZIF-8 showing the strongest inhibition. Data in Fig. 5C is presented as mean ± SD, n = 3 for each group. *p < 0.05, **p < 0.01, ***p < 0.001, ****p < 0.0001
Fig. 5 Mino@ZIF-8/SF microneedles attenuate C. acnes-induced transcriptional activation and inflammatory signaling in SZ95 sebocytes. (A) RNA-seq heatmap showing HKC-induced upregulation of representative inflammatory genes and their suppression by Mino@ZIF-8/SF MNs. (B) KEGG enrichment analysis showing red-labeled core inflammatory pathways relevant to acne that were attenuated by MN treatment, and green-labeled regulatory or metabolic pathways representing potential targets for future therapeutic intervention. (C) qPCR quantification of NFKB1 expression across groups, showing HKC-induced transcriptional upregulation partially normalized by Mino@ZIF-8/SF MN extracts. (D) qPCR validation of IL-1α, IL-1β, IL-6, IL-8, and MMP9 in different treatment groups, with Mino@ZIF-8 showing the strongest inhibition. Data in Fig. 5C is presented as mean ± SD, n = 3 for each group. *p < 0.05, **p < 0.01, ***p < 0.001, ****p < 0.0001CC BY-NC-ND · PubMed Central
Fig. 6 Scratch wound healing assay of HaCaT and HSF cells treated with microneedle extracts. (A) Representative images of HaCaT (left) and HSF (right) monolayers at the indicated time points (0, 12, and 24 h for HaCaT; 0, 24, and 48 h for HSF) after scratching and incubation with Control medium, SF MN extract, or Mino@ZIF-8/SF MN extract. Yellow lines denote wound edges. (B) Quantification of wound closure percentage for each group. Data are shown as mean ± SD (n = 3). *p < 0.05, **p < 0.01, ****p < 0.0001
Fig. 6 Scratch wound healing assay of HaCaT and HSF cells treated with microneedle extracts. (A) Representative images of HaCaT (left) and HSF (right) monolayers at the indicated time points (0, 12, and 24 h for HaCaT; 0, 24, and 48 h for HSF) after scratching and incubation with Control medium, SF MN extract, or Mino@ZIF-8/SF MN extract. Yellow lines denote wound edges. (B) Quantification of wound closure percentage for each group. Data are shown as mean ± SD (n = 3). *p < 0.05, **p < 0.01, ****p < 0.0001CC BY-NC-ND · PubMed Central
Fig. 7 Therapeutic efficacy of Mino@ZIF-8/SF MNs in a C. acnes-induced acne-like lesion mouse model. (A) Schematic of experimental timeline: artificial sebum was applied daily from day −5, C. acnes was injected intradermally on day −2, and treatments were administered on day 0, 2 and 4. Acne samples were collected on day 7 and subsequent histology was performed. (B) Representative images of lesions in each group at indicated time points. (C-E) Quantitative evaluation of lesion severity using the Leeds revised acne grading system: (C) elevation score, (D) eschar score, and (E) diameter score. Data are mean ± SD. Figure 7A was created with BioRender.com
Fig. 7 Therapeutic efficacy of Mino@ZIF-8/SF MNs in a C. acnes-induced acne-like lesion mouse model. (A) Schematic of experimental timeline: artificial sebum was applied daily from day −5, C. acnes was injected intradermally on day −2, and treatments were administered on day 0, 2 and 4. Acne samples were collected on day 7 and subsequent histology was performed. (B) Representative images of lesions in each group at indicated time points. (C-E) Quantitative evaluation of lesion severity using the Leeds revised acne grading system: (C) elevation score, (D) eschar score, and (E) diameter score. Data are mean ± SD. Figure 7A was created with BioRender.comCC BY-NC-ND · PubMed Central
Fig. 8 Histological and lipid staining analysis of mouse dorsal skin post-treatments. (A) Representative images of H&E staining showing epidermal morphology, BODIPY staining (green) indicating sebaceous lipid droplets, and Oil Red O staining (red) visualizing neutral lipids in sebaceous glands across groups. Scale bars: 100 μm. (B) Quantitative analysis of epidermal thickness (µm), BODIPY fluorescence intensity (a.u.), and Oil Red O-positive area (%). Data are expressed as mean ± SD (n = 3–5 per group). *p < 0.05, **p < 0.01
Fig. 8 Histological and lipid staining analysis of mouse dorsal skin post-treatments. (A) Representative images of H&E staining showing epidermal morphology, BODIPY staining (green) indicating sebaceous lipid droplets, and Oil Red O staining (red) visualizing neutral lipids in sebaceous glands across groups. Scale bars: 100 μm. (B) Quantitative analysis of epidermal thickness (µm), BODIPY fluorescence intensity (a.u.), and Oil Red O-positive area (%). Data are expressed as mean ± SD (n = 3–5 per group). *p < 0.05, **p < 0.01CC BY-NC-ND · PubMed Central
Fig. 9 In vivo biosafety evaluation of Mino@ZIF-8/SF MNs. (A) Representative H&E-stained sections of major organs (heart, liver, spleen, lung, kidney) from mice in each treatment group after 7 days, showing preserved tissue morphology and absence of pathological changes. Scale bars: 100 μm. (B) Hematological and serum biochemical analyses, including WBC, RBC, HGB, MCH, PLT, ALT, AST, CREA, and UA, revealed no significant differences (n.s.) between treated and control groups, indicating no systemic toxicity. Data are mean ± SD, n = 3
Fig. 9 In vivo biosafety evaluation of Mino@ZIF-8/SF MNs. (A) Representative H&E-stained sections of major organs (heart, liver, spleen, lung, kidney) from mice in each treatment group after 7 days, showing preserved tissue morphology and absence of pathological changes. Scale bars: 100 μm. (B) Hematological and serum biochemical analyses, including WBC, RBC, HGB, MCH, PLT, ALT, AST, CREA, and UA, revealed no significant differences (n.s.) between treated and control groups, indicating no systemic toxicity. Data are mean ± SD, n = 3CC BY-NC-ND · PubMed Central

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Metadata

Authors
Yang, X., Ruan, D., Ye, F., Qiu, X., Li, S., Huang, L., Zouboulis, C. C., Mo, X., Jiang, X., & Ju, Q.
Affiliations
  • Shanghai Jiao Tong University (CN)
  • Second Military Medical University (CN)
  • Medizinische Hochschule Brandenburg Theodor Fontane (DE)
  • Peking University (CN)
Corresponding author
  • Mo, Xiaohui
  • Jiang, Xiping
  • Ju, Qiang
ORCID
Venue
Journal of Nanobiotechnology
Publisher
Springer Science and Business Media LLC
Published
2026-03-11
Volume
24
Issue
1
ISSN
1477-3155 (ISSN-L)
DOI
10.1186/s12951-026-04221-8
PMC
PMC13088723
OpenAlex
W7134971378
Semantic Scholar
29bda12fd7fd0e4e276bd5440c5e0461dcc2ad85
Cited by
4
References
63
Citations by year
2026: 4
FWCI
11.40
Type
journal article
Language
en
Open access
Licence
Locations
  • Journal of Nanobiotechnology (publishedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
National Key Research and Development Program of China
Topics
  • Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmaceutical Science › Advancements in Transdermal Drug Delivery
  • Health Sciences › Medicine › Dermatology › Acne and Rosacea Treatments and Effects
  • Physical Sciences › Materials Science › Biomaterials › Silk-based biomaterials and applications
Keywords
acne, minocycline, ZIF-8, metal-organic frameworks, pH-responsive drug delivery, sebocytes, Propionibacterium acnes, antibiotic therapy, anti-inflammatory activity, PPARγ, lipid droplet accumulation, transdermal drug delivery, dissolving microneedles
MeSH terms
Metal-Organic Frameworks, Microneedle Drug Delivery, Acne Vulgaris, Animals, Anti-Bacterial Agents, Fibroins, Humans, Hydrogen-Ion Concentration, Imidazoles, Minocycline, Propionibacterium acnes, Sebaceous Glands, Zeolites, Silk, Mice, Nanoparticles

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CoChat. (2026). Citation check: Dissolvable silk microneedles delivering minocycline-loaded ZIF-8 nanoparticles for targeted modulation of sebocyte metabolism and improved acne therapy. https://app.cochat.ai/papers/10.1186/s12951-026-04221-8
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Yang, X., Ruan, D., Ye, F., Qiu, X., Li, S., Huang, L., Zouboulis, C. C., Mo, X., Jiang, X., & Ju, Q. (2026). Dissolvable silk microneedles delivering minocycline-loaded ZIF-8 nanoparticles for targeted modulation of sebocyte metabolism and improved acne therapy. Journal of Nanobiotechnology. https://doi.org/10.1186/s12951-026-04221-8

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