Delivery of FGF18 using mRNA-LNP protects the cartilage against degeneration via alleviating chondrocyte senescence
Abstract Background Osteoarthritis (OA) is a degenerative joint disease with an immense unmet medical need. FGF18 protein is a potential regenerative factor for cartilage repair. However, traditional protein delivery methods have limited efficacy due to the short lifetime and shallow infiltration. R...
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BMC
2025-01-01
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| Series: | Journal of Nanobiotechnology |
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| Online Access: | https://doi.org/10.1186/s12951-025-03103-9 |
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| author | Keyu Kong Baixing Li Yongyun Chang Chen Zhao Hua Qiao Minghao Jin Xinru Wu Wenxuan Fan Liao Wang Yansong Qi Yongsheng Xu Zanjing Zhai Peixiang Ma Huiwu Li |
| author_facet | Keyu Kong Baixing Li Yongyun Chang Chen Zhao Hua Qiao Minghao Jin Xinru Wu Wenxuan Fan Liao Wang Yansong Qi Yongsheng Xu Zanjing Zhai Peixiang Ma Huiwu Li |
| author_sort | Keyu Kong |
| collection | DOAJ |
| description | Abstract Background Osteoarthritis (OA) is a degenerative joint disease with an immense unmet medical need. FGF18 protein is a potential regenerative factor for cartilage repair. However, traditional protein delivery methods have limited efficacy due to the short lifetime and shallow infiltration. Results In this work, we discovered that lipid nanoparticle (LNP) can infiltrate and deliver FGF18 mRNA deeper in the cartilage than proteins. After mRNA UTR optimization and chemical modification, the expression of FGF18 can last up to 6 days in the cartilage. Furthermore, delivering FGF18 mRNA activates FOXO3a-autophagy pathway, which protects against chondrocyte degeneration and senescence. Local intra-articular injection of FGF18 mRNA-LNP significantly alleviates OA symptoms in DMM and senile OA models. Sustained expression and accessibility of FGF18-mRNA to deeper chondrocytes makes LNP-mRNA more effective than FGF18 recombinant protein. Conclusions In summary, this study presents a novel approach superior to recombinant protein alone and holds promise as a new therapeutic strategy for OA. Graphical abstract |
| format | Article |
| id | doaj-art-3410cc005a0449799dacda2c2b31756a |
| institution | Kabale University |
| issn | 1477-3155 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Nanobiotechnology |
| spelling | doaj-art-3410cc005a0449799dacda2c2b31756a2025-01-26T12:50:56ZengBMCJournal of Nanobiotechnology1477-31552025-01-0123112110.1186/s12951-025-03103-9Delivery of FGF18 using mRNA-LNP protects the cartilage against degeneration via alleviating chondrocyte senescenceKeyu Kong0Baixing Li1Yongyun Chang2Chen Zhao3Hua Qiao4Minghao Jin5Xinru Wu6Wenxuan Fan7Liao Wang8Yansong Qi9Yongsheng Xu10Zanjing Zhai11Peixiang Ma12Huiwu Li13Shanghai Key Laboratory of Orthopaedic Implants, Department of Orthopaedic Surgery, Shanghai Ninth People’s Hospital, Shanghai Jiaotong University School of MedicineShanghai Key Laboratory of Orthopaedic Implants, Department of Orthopaedic Surgery, Shanghai Ninth People’s Hospital, Shanghai Jiaotong University School of MedicineShanghai Key Laboratory of Orthopaedic Implants, Department of Orthopaedic Surgery, Shanghai Ninth People’s Hospital, Shanghai Jiaotong University School of MedicineShanghai Key Laboratory of Orthopaedic Implants, Department of Orthopaedic Surgery, Shanghai Ninth People’s Hospital, Shanghai Jiaotong University School of MedicineShanghai Key Laboratory of Orthopaedic Implants, Department of Orthopaedic Surgery, Shanghai Ninth People’s Hospital, Shanghai Jiaotong University School of MedicineShanghai Key Laboratory of Orthopaedic Implants, Department of Orthopaedic Surgery, Shanghai Ninth People’s Hospital, Shanghai Jiaotong University School of MedicineShanghai Key Laboratory of Orthopaedic Implants, Department of Orthopaedic Surgery, Shanghai Ninth People’s Hospital, Shanghai Jiaotong University School of MedicineShanghai Key Laboratory of Orthopaedic Implants, Department of Orthopaedic Surgery, Shanghai Ninth People’s Hospital, Shanghai Jiaotong University School of MedicineShanghai Key Laboratory of Orthopaedic Implants, Department of Orthopaedic Surgery, Shanghai Ninth People’s Hospital, Shanghai Jiaotong University School of MedicineOrthopedic Center (Sports Medicine Center), Inner Mongolia People’s HospitalOrthopedic Center (Sports Medicine Center), Inner Mongolia People’s HospitalShanghai Key Laboratory of Orthopaedic Implants, Department of Orthopaedic Surgery, Shanghai Ninth People’s Hospital, Shanghai Jiaotong University School of MedicineShanghai Key Laboratory of Orthopaedic Implants, Department of Orthopaedic Surgery, Shanghai Ninth People’s Hospital, Shanghai Jiaotong University School of MedicineShanghai Key Laboratory of Orthopaedic Implants, Department of Orthopaedic Surgery, Shanghai Ninth People’s Hospital, Shanghai Jiaotong University School of MedicineAbstract Background Osteoarthritis (OA) is a degenerative joint disease with an immense unmet medical need. FGF18 protein is a potential regenerative factor for cartilage repair. However, traditional protein delivery methods have limited efficacy due to the short lifetime and shallow infiltration. Results In this work, we discovered that lipid nanoparticle (LNP) can infiltrate and deliver FGF18 mRNA deeper in the cartilage than proteins. After mRNA UTR optimization and chemical modification, the expression of FGF18 can last up to 6 days in the cartilage. Furthermore, delivering FGF18 mRNA activates FOXO3a-autophagy pathway, which protects against chondrocyte degeneration and senescence. Local intra-articular injection of FGF18 mRNA-LNP significantly alleviates OA symptoms in DMM and senile OA models. Sustained expression and accessibility of FGF18-mRNA to deeper chondrocytes makes LNP-mRNA more effective than FGF18 recombinant protein. Conclusions In summary, this study presents a novel approach superior to recombinant protein alone and holds promise as a new therapeutic strategy for OA. Graphical abstracthttps://doi.org/10.1186/s12951-025-03103-9OsteoarthritisFGF18mRNALipid nanoparticlesAutophagy |
| spellingShingle | Keyu Kong Baixing Li Yongyun Chang Chen Zhao Hua Qiao Minghao Jin Xinru Wu Wenxuan Fan Liao Wang Yansong Qi Yongsheng Xu Zanjing Zhai Peixiang Ma Huiwu Li Delivery of FGF18 using mRNA-LNP protects the cartilage against degeneration via alleviating chondrocyte senescence Journal of Nanobiotechnology Osteoarthritis FGF18 mRNA Lipid nanoparticles Autophagy |
| title | Delivery of FGF18 using mRNA-LNP protects the cartilage against degeneration via alleviating chondrocyte senescence |
| title_full | Delivery of FGF18 using mRNA-LNP protects the cartilage against degeneration via alleviating chondrocyte senescence |
| title_fullStr | Delivery of FGF18 using mRNA-LNP protects the cartilage against degeneration via alleviating chondrocyte senescence |
| title_full_unstemmed | Delivery of FGF18 using mRNA-LNP protects the cartilage against degeneration via alleviating chondrocyte senescence |
| title_short | Delivery of FGF18 using mRNA-LNP protects the cartilage against degeneration via alleviating chondrocyte senescence |
| title_sort | delivery of fgf18 using mrna lnp protects the cartilage against degeneration via alleviating chondrocyte senescence |
| topic | Osteoarthritis FGF18 mRNA Lipid nanoparticles Autophagy |
| url | https://doi.org/10.1186/s12951-025-03103-9 |
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