Microneedle-assisted dual delivery of PUMA gene and celastrol for synergistic therapy of rheumatoid arthritis through restoring synovial homeostasis
Abnormal proliferation of aggressive fibroblast-like synoviocytes (FLS) and perpetuate synovial inflammation can inevitably accelerate the progression of rheumatoid arthritis (RA). Herein, a strategy of simultaneously promoting FLS apoptosis and inhibiting inflammation as mediated by macrophages is...
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| Format: | Article |
| Language: | English |
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KeAi Communications Co., Ltd.
2024-06-01
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| Series: | Bioactive Materials |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2452199X24000756 |
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| author | Peng Hua Ruifeng Liang Suleixin Yang Yanbei Tu Meiwan Chen |
| author_facet | Peng Hua Ruifeng Liang Suleixin Yang Yanbei Tu Meiwan Chen |
| author_sort | Peng Hua |
| collection | DOAJ |
| description | Abnormal proliferation of aggressive fibroblast-like synoviocytes (FLS) and perpetuate synovial inflammation can inevitably accelerate the progression of rheumatoid arthritis (RA). Herein, a strategy of simultaneously promoting FLS apoptosis and inhibiting inflammation as mediated by macrophages is proposed to restore synovial homeostasis for effective RA therapy. A hyaluronic acid-based dissolvable microneedle (MN) is fabricated for transdermal delivery of dual human serum albumin (HSA)-contained biomimetic nanocomplexes to regulate RA FLS and macrophages. Upon skin insertion, dual nanocomplexes are released rapidly from the MN and accumulate in RA joint microenvironment through both passive and active targeting as mediated by HSA. Thioketal-crosslinked fluorinated polyethyleneimine 1.8 K (TKPF) was constructed to bind the plasmid encoding pro-apoptotic gene PUMA with HSA coating layer (TKPF/pPUMA@HSA, TPH). TPH nanocomplexes can upregulate PUMA through RA FLS transfection to trigger efficient apoptosis. Also, HSA nanocomplexes encapsulating the classic anti-inflammatory natural product celastrol (Cel@HSA, CH) can inhibit inflammation of macrophages through blocking NF-κB pathway activation. TPH/CH MN can deplete RA FLS and inhibit M1 macrophage activation, suppress synovial hyperplasia as well as reduce bone and cartilage erosion in a collagen-induced arthritis (CIA) mouse model, demonstrating a promising strategy for efficient RA treatment. |
| first_indexed | 2024-03-07T18:36:06Z |
| format | Article |
| id | doaj.art-4a66ba84ac64424cb7dfcb80de756935 |
| institution | Directory Open Access Journal |
| issn | 2452-199X |
| language | English |
| last_indexed | 2024-03-07T18:36:06Z |
| publishDate | 2024-06-01 |
| publisher | KeAi Communications Co., Ltd. |
| record_format | Article |
| series | Bioactive Materials |
| spelling | doaj.art-4a66ba84ac64424cb7dfcb80de7569352024-03-02T04:54:36ZengKeAi Communications Co., Ltd.Bioactive Materials2452-199X2024-06-01368395Microneedle-assisted dual delivery of PUMA gene and celastrol for synergistic therapy of rheumatoid arthritis through restoring synovial homeostasisPeng Hua0Ruifeng Liang1Suleixin Yang2Yanbei Tu3Meiwan Chen4State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macau SAR, ChinaState Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macau SAR, ChinaState Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macau SAR, ChinaState Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macau SAR, ChinaCorresponding author.; State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macau SAR, ChinaAbnormal proliferation of aggressive fibroblast-like synoviocytes (FLS) and perpetuate synovial inflammation can inevitably accelerate the progression of rheumatoid arthritis (RA). Herein, a strategy of simultaneously promoting FLS apoptosis and inhibiting inflammation as mediated by macrophages is proposed to restore synovial homeostasis for effective RA therapy. A hyaluronic acid-based dissolvable microneedle (MN) is fabricated for transdermal delivery of dual human serum albumin (HSA)-contained biomimetic nanocomplexes to regulate RA FLS and macrophages. Upon skin insertion, dual nanocomplexes are released rapidly from the MN and accumulate in RA joint microenvironment through both passive and active targeting as mediated by HSA. Thioketal-crosslinked fluorinated polyethyleneimine 1.8 K (TKPF) was constructed to bind the plasmid encoding pro-apoptotic gene PUMA with HSA coating layer (TKPF/pPUMA@HSA, TPH). TPH nanocomplexes can upregulate PUMA through RA FLS transfection to trigger efficient apoptosis. Also, HSA nanocomplexes encapsulating the classic anti-inflammatory natural product celastrol (Cel@HSA, CH) can inhibit inflammation of macrophages through blocking NF-κB pathway activation. TPH/CH MN can deplete RA FLS and inhibit M1 macrophage activation, suppress synovial hyperplasia as well as reduce bone and cartilage erosion in a collagen-induced arthritis (CIA) mouse model, demonstrating a promising strategy for efficient RA treatment.http://www.sciencedirect.com/science/article/pii/S2452199X24000756Rheumatoid arthritisPUMACelastrolAnti-inflammationFibroblast-like synoviocyte apoptosis |
| spellingShingle | Peng Hua Ruifeng Liang Suleixin Yang Yanbei Tu Meiwan Chen Microneedle-assisted dual delivery of PUMA gene and celastrol for synergistic therapy of rheumatoid arthritis through restoring synovial homeostasis Bioactive Materials Rheumatoid arthritis PUMA Celastrol Anti-inflammation Fibroblast-like synoviocyte apoptosis |
| title | Microneedle-assisted dual delivery of PUMA gene and celastrol for synergistic therapy of rheumatoid arthritis through restoring synovial homeostasis |
| title_full | Microneedle-assisted dual delivery of PUMA gene and celastrol for synergistic therapy of rheumatoid arthritis through restoring synovial homeostasis |
| title_fullStr | Microneedle-assisted dual delivery of PUMA gene and celastrol for synergistic therapy of rheumatoid arthritis through restoring synovial homeostasis |
| title_full_unstemmed | Microneedle-assisted dual delivery of PUMA gene and celastrol for synergistic therapy of rheumatoid arthritis through restoring synovial homeostasis |
| title_short | Microneedle-assisted dual delivery of PUMA gene and celastrol for synergistic therapy of rheumatoid arthritis through restoring synovial homeostasis |
| title_sort | microneedle assisted dual delivery of puma gene and celastrol for synergistic therapy of rheumatoid arthritis through restoring synovial homeostasis |
| topic | Rheumatoid arthritis PUMA Celastrol Anti-inflammation Fibroblast-like synoviocyte apoptosis |
| url | http://www.sciencedirect.com/science/article/pii/S2452199X24000756 |
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