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Cited by 198Nanoparticle-Based Drug DeliveryExtracellular vesicles in diseaseRheumatoid Arthritis Research and Therapies

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Exosome-based biomimetic nanoparticles targeted to inflamed joints for enhanced treatment of rheumatoid arthritis

Open access
Yan, Feili, Zhong, Zhirong, Wang, Yao, Feng, Yue, Mei, Zhiqiang, Li, Hui, Chen, Xiang, Cai, Liang, Li, Chunhong·2020·Journal of Nanobiotechnology
DOI 10.1186/s12951-020-00675-6PMC PMC7441703

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Abstract

BACKGROUND: Glucocorticoids (GCs) show powerful treatment effect on rheumatoid arthritis (RA). However, the clinical application is limited by their nonspecific distribution after systemic administration, serious adverse reactions during long-term administration. To achieve better treatment, reduce side effect, we here established a biomimetic exosome (Exo) encapsulating dexamethasone sodium phosphate (Dex) nanoparticle (Exo/Dex), whose surface was modified with folic acid (FA)-polyethylene glycol (PEG)-cholesterol (Chol) compound to attain FPC-Exo/Dex active targeting drug delivery system. RESULTS: The size of FPC-Exo/Dex was 128.43 ± 16.27 nm, with a polydispersity index (PDI) of 0.36 ± 0.05, and the Zeta potential was - 22.73 ± 0.91 mV. The encapsulation efficiency (EE) of the preparation was 10.26 ± 0.73%, with drug loading efficiency (DLE) of 18.81 ± 2.05%. In vitro study showed this system displayed enhanced endocytosis and excellent anti-inflammation effect against RAW264.7 cells by suppressing pro-inflammatory cytokines and increasing anti-inflammatory cytokine. Further biodistribution study showed the fluorescence intensity of FPC-Exo/Dex was stronger than other Dex formulations in joints, suggesting its enhanced accumulation to inflammation sites. In vivo biodistribution experiment displayed FPC-Exo/Dex could preserve the bone and cartilage of CIA mice better and significantly reduce inflamed joints. Next in vivo safety evaluation demonstrated this biomimetic drug delivery system had no obvious hepatotoxicity and exhibited desirable biocompatibility. CONCLUSION: The present study provides a promising strategy for using exosome as nanocarrier to enhance the therapeutic effect of GCs against RA.

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Fig. 1 Characterization of exosomes. a Size, PDI and zeta potential of Exos. b Size distribution of Exos. c Transmission electron micrographs of Exos. e Western blot to confirm the expression of CD9 and CD63
Fig. 1 Characterization of exosomes. a Size, PDI and zeta potential of Exos. b Size distribution of Exos. c Transmission electron micrographs of Exos. e Western blot to confirm the expression of CD9 and CD63CC BY · PubMed Central
Fig. 2 Characterization of Exo/Dex, FPC-Exo/Dex and Lip/Dex. a Size, PDI, zeta potential, EE and DLE of Dex preparations. Size distribution of Exo/Dex b, FPC-Exo/Dex c and Lip/Dex d. Transmission electron micrographs of Exo/Dex e, FPC-Exo/Dex f and Lip/Dex g
Fig. 2 Characterization of Exo/Dex, FPC-Exo/Dex and Lip/Dex. a Size, PDI, zeta potential, EE and DLE of Dex preparations. Size distribution of Exo/Dex b, FPC-Exo/Dex c and Lip/Dex d. Transmission electron micrographs of Exo/Dex e, FPC-Exo/Dex f and Lip/Dex gCC BY · PubMed Central
Fig. 3 In vitro cumulative release and toxicity of Dex preparations. Cumulative release of Dex from Lip/Dex, Exo/Dex and FPC-Exo/Dex at PBS of pH 7.4 a or pH 6.0 b. Results were shown as mean ± SD (n = 3). The effect of Dex, Lip/Dex, Exo/Dex and FPC-Exo/Dex for HUVEC c and RAW264.7 cells viability d. Data represent mean ± SD (n = 5)
Fig. 3 In vitro cumulative release and toxicity of Dex preparations. Cumulative release of Dex from Lip/Dex, Exo/Dex and FPC-Exo/Dex at PBS of pH 7.4 a or pH 6.0 b. Results were shown as mean ± SD (n = 3). The effect of Dex, Lip/Dex, Exo/Dex and FPC-Exo/Dex for HUVEC c and RAW264.7 cells viability d. Data represent mean ± SD (n = 5)CC BY · PubMed Central
Fig. 4 Uptake of Lip/Dex, Exo/Dex and FPC-Exo/Dex by RAW264.7 with or without LPS activation. a Representative images of Flow cytometry analysis showing uptake of Dex preparations labeled by PKH 67 in RAW264.7 cells with or without LPS activation. b Uptake rate of different Dex preparations by flow cytometry (n = 3, **p < 0.01, ****p < 0.0001 vs cells treated with FPC-Exo/Dex, #p < 0.05, ##p < 0.01 are cells treated with Lip/Dex compared to Exo/Dex). c Confocal microscopy showing uptake of different Dex preparations labeled by PKH 67 in RAW264.7 cells without LPS activation. Dex preparations appear in red; nucleus, blue; and cytoplasm, green. Scale bar, 20 μm. d Confocal microscopy showing uptake of different Dex preparations labeled by PKH 67 in RAW264.7 cells without LPS activation. Dex preparations appear in red; nucleus, blue; and cytoplasm, green. Scale bar, 20 μm
Fig. 4 Uptake of Lip/Dex, Exo/Dex and FPC-Exo/Dex by RAW264.7 with or without LPS activation. a Representative images of Flow cytometry analysis showing uptake of Dex preparations labeled by PKH 67 in RAW264.7 cells with or without LPS activation. b Uptake rate of different Dex preparations by flow cytometry (n = 3, **p < 0.01, ****p < 0.0001 vs cells treated with FPC-Exo/Dex, #p < 0.05, ##p < 0.01 are cells treated with Lip/Dex compared to Exo/Dex). c Confocal microscopy showing uptake of different Dex preparations labeled by PKH 67 in RAW264.7 cells without LPS activation. Dex preparations appear in red; nucleus, blue; and cytoplasm, green. Scale bar, 20 μm. d Confocal microscopy showing uptake of different Dex preparations labeled by PKH 67 in RAW264.7 cells without LPS activation. Dex preparations appear in red; nucleus, blue; and cytoplasm, green. Scale bar, 20 μmCC BY · PubMed Central
Fig. 5 Expression of inflammatory cytokines in cell-free supernatants treated with different preparations. Level of a TNF-α, b IL-1β, and c IL-10 (n = 3, *p < 0.05, **p < 0.01, ***p < 0.001 vs cells treated with PBS, #p < 0.05, ###p < 0.001 are cells treated with Lip/Dex compared to Exo/Dex)
Fig. 5 Expression of inflammatory cytokines in cell-free supernatants treated with different preparations. Level of a TNF-α, b IL-1β, and c IL-10 (n = 3, *p < 0.05, **p < 0.01, ***p < 0.001 vs cells treated with PBS, #p < 0.05, ###p < 0.001 are cells treated with Lip/Dex compared to Exo/Dex)CC BY · PubMed Central
Fig. 6 The real-time fluorescence imaging of CIA mice. a Real-time fluorescence imaging of CIA mice after intravenous injection with free DID, DID/Lip/Dex, DID/Exo/Dex and DID/FPC-Exo/Dex, respectively (n = 3). b Ex vivo imaging of the plasma and organs at 24 h after intravenous injection. c Semi-quantitation of fluorescence intensity in joints. d Semi-quantitation of fluorescence intensity in joints in plasma and organs (n = 3, *p < 0.05, **p < 0.01, ***p < 0.001, ****p < 0.0001 vs mice injectedted with DID/FPC-Exo/Dex, #p < 0.05, ##p < 0.01, ###p < 0.001 are mice injected with DID/Lip/Dex compared to DID/Exo/Dex)
Fig. 6 The real-time fluorescence imaging of CIA mice. a Real-time fluorescence imaging of CIA mice after intravenous injection with free DID, DID/Lip/Dex, DID/Exo/Dex and DID/FPC-Exo/Dex, respectively (n = 3). b Ex vivo imaging of the plasma and organs at 24 h after intravenous injection. c Semi-quantitation of fluorescence intensity in joints. d Semi-quantitation of fluorescence intensity in joints in plasma and organs (n = 3, *p < 0.05, **p < 0.01, ***p < 0.001, ****p < 0.0001 vs mice injectedted with DID/FPC-Exo/Dex, #p < 0.05, ##p < 0.01, ###p < 0.001 are mice injected with DID/Lip/Dex compared to DID/Exo/Dex)CC BY · PubMed Central
Fig. 7 Therapeutic indicators monitoring during treatment. Measurement of body weight a, articular score b, paw thicknessc, paw volume d and photographs of representative hind limbs from animals treated with various Dex formulations in CIA mice e. (n = 3, *p < 0.05, **p < 0.01, ***p < 0.001, ****p < 0.0001 vs mice injected with Saline)
Fig. 7 Therapeutic indicators monitoring during treatment. Measurement of body weight a, articular score b, paw thicknessc, paw volume d and photographs of representative hind limbs from animals treated with various Dex formulations in CIA mice e. (n = 3, *p < 0.05, **p < 0.01, ***p < 0.001, ****p < 0.0001 vs mice injected with Saline)CC BY · PubMed Central
Fig. 8 Micro-CT analyses of the hind limbs of the mice from different treatment groups. a Representative 3D reconstructed images from each treatment group. b–g Bone morphometric parameters of ROI within calcaneus bone (n = 3, *p < 0.05, **p < 0.01, ***p < 0.001, ****p < 0.0001 vs mice treated with Saline, #p < 0.05 is mice treated with Lip/Dex compared to Exo/Dex)
Fig. 8 Micro-CT analyses of the hind limbs of the mice from different treatment groups. a Representative 3D reconstructed images from each treatment group. b–g Bone morphometric parameters of ROI within calcaneus bone (n = 3, *p < 0.05, **p < 0.01, ***p < 0.001, ****p < 0.0001 vs mice treated with Saline, #p < 0.05 is mice treated with Lip/Dex compared to Exo/Dex)CC BY · PubMed Central
Fig. 9 Histopathology analysis of the ankle joints. a Representative histopathology pictures of H&E staining. b Representative histopathology pictures of SO staining. c Histopathology scores of H&E staining (n = 3, **p < 0.01, ***p < 0.001 vs mice treated with Saline, #p < 0.05 is mice treated with Lip/Dex compared to with Exo/Dex)
Fig. 9 Histopathology analysis of the ankle joints. a Representative histopathology pictures of H&E staining. b Representative histopathology pictures of SO staining. c Histopathology scores of H&E staining (n = 3, **p < 0.01, ***p < 0.001 vs mice treated with Saline, #p < 0.05 is mice treated with Lip/Dex compared to with Exo/Dex)CC BY · PubMed Central
Fig. 10 Levels of the inflammatory cytokines in serum. Level of TNF-α a, IL-1β b, and IL-10 c, results are shown as mean ± SD (n = 3, *p < 0.05, **p < 0.01, ***p < 0.001 vs mice treated with Saline, #p < 0.05 is mice treated with Lip/Dex compared to Exo/Dex)
Fig. 10 Levels of the inflammatory cytokines in serum. Level of TNF-α a, IL-1β b, and IL-10 c, results are shown as mean ± SD (n = 3, *p < 0.05, **p < 0.01, ***p < 0.001 vs mice treated with Saline, #p < 0.05 is mice treated with Lip/Dex compared to Exo/Dex)CC BY · PubMed Central
Fig. 11 Levels of AST and ALT in serum (n = 3). All the treatment groups were compared to Normal group
Fig. 11 Levels of AST and ALT in serum (n = 3). All the treatment groups were compared to Normal groupCC BY · PubMed Central

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Metadata

Authors
Yan, F., Zhong, Z., Wang, Y., Feng, Y., Mei, Z., Li, H., Chen, X., Cai, L., & Li, C.
Affiliations
  • Southwest Medical University (CN)
  • Affiliated Hospital of Southwest Medical University (CN)
  • Sichuan University (CN)
Corresponding author
  • Cai, Liang
  • Li, Chunhong
ORCID
Venue
Journal of Nanobiotechnology
Publisher
Springer Science and Business Media LLC
Published
2020-08-20
Volume
18
Issue
1
Pages
115-115
ISSN
1477-3155 (ISSN-L)
DOI
10.1186/s12951-020-00675-6
PMC
PMC7441703
OpenAlex
W3050111167
Cited by
197
References
54
Citations by year
2026: 18 · 2025: 36 · 2024: 43 · 2023: 36 · 2022: 39 · 2021: 24 · 2020: 1
FWCI
6.50
Type
journal article
Language
en
Open access
Licence
Locations
  • Journal of Nanobiotechnology (publishedVersion, cc-by)
  • Research Square (acceptedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
National Major Science and Technology Projects of China (81803478)
Topics
  • Physical Sciences › Materials Science › Biomaterials › Nanoparticle-Based Drug Delivery
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Extracellular vesicles in disease
  • Health Sciences › Medicine › Rheumatology › Rheumatoid Arthritis Research and Therapies
Keywords
rheumatoid arthritis, exosomes, biomimetic nanoparticles, dexamethasone, glucocorticoids, targeted drug delivery, folic acid, joint inflammation, anti-inflammatory cytokines, collagen-induced arthritis, tissue distribution, biocompatibility, nanocarriers
MeSH terms
RAW 264.7 Cells, Animals, Anti-Inflammatory Agents, Arthritis, Rheumatoid, Cholesterol, Dexamethasone, Folic Acid, Joints, Male, Polyethylene Glycols, Biomimetic Materials, Mice, Nanoparticles, Exosomes

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