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经关节腔注射载 FGF18 mRNA 脂质纳米颗粒治疗骨关节炎。

Targeted Therapy of Osteoarthritis via Intra-Articular Delivery of Lipid-Nanoparticle-Encapsulated Recombinant Human FGF18 mRNA.

机构信息

Department of Sports Medicine, Institute of Sports Medicine of Peking University, Beijing Key Laboratory of Sports Injuries, Peking University Third Hospital, Beijing, 100191, China.

Engineering Research Center of Sports Trauma Treatment Technology and Devices, Ministry of Education, Beijing, 100191, China.

出版信息

Adv Healthc Mater. 2024 Nov;13(29):e2400804. doi: 10.1002/adhm.202400804. Epub 2024 Oct 4.

DOI:10.1002/adhm.202400804
PMID:39363784
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11582510/
Abstract

Fibroblast growth factor 18 (FGF18) emerges as a promising therapeutic target for osteoarthritis (OA). In this study, a novel articular cavity-localized lipid nanoparticle (LNP) named WG-PL14 is developed. This optimized formulation has a nearly 30-fold increase in mRNA expression as well as better articular cavity enrichment compared to commercial lipids MC3 when performing intra-articular injection. Then, a mRNA sequence encoding recombinant human FGF18 (rhFGF18) for potential mRNA therapy in OA is optimized. In vitro assays confirm the translation of rhFGF18 mRNA into functional proteins within rat and human chondrocytes, promoting cell proliferation and extracellular matrix (ECM) synthesis. Subsequently, the therapeutic efficacy of the LNP-rhFGF18 mRNA complex is systematically assessed in a mouse OA model. The administration exhibits several positive outcomes, including an improved pain response, upregulation of ECM-related genes (e.g., AGRN and HAS2), and remodeling of subchondral bone homeostasis compared to a control group. Taken together, these findings underscore the potential of localized LNP-rhFGF18 mRNA therapy in promoting the regeneration of cartilage tissue and mitigating the progression of OA.

摘要

成纤维细胞生长因子 18（FGF18）作为骨关节炎（OA）的一种有前途的治疗靶点而备受关注。在本研究中，开发了一种新型的关节腔局部脂质纳米颗粒（LNP），命名为 WG-PL14。与商业脂质 MC3 相比，这种优化配方在进行关节内注射时，mRNA 表达增加近 30 倍，并且在关节腔内的富集程度更好。然后，对编码重组人成纤维细胞生长因子 18（rhFGF18）的 mRNA 序列进行优化，以用于 OA 的潜在 mRNA 治疗。体外实验证实，rhFGF18 mRNA 在大鼠和人软骨细胞内翻译成有功能的蛋白质，促进细胞增殖和细胞外基质（ECM）合成。随后，在小鼠 OA 模型中系统评估了 LNP-rhFGF18 mRNA 复合物的治疗效果。与对照组相比，该给药方案表现出多种积极的结果，包括改善疼痛反应、上调 ECM 相关基因（如 AGRN 和 HAS2）以及重塑软骨下骨稳态。综上所述，这些发现强调了局部 LNP-rhFGF18 mRNA 治疗在促进软骨组织再生和减轻 OA 进展方面的潜力。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ad39/11582510/f2001488f384/ADHM-13-0-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ad39/11582510/205fec64fb53/ADHM-13-0-g003.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ad39/11582510/7c4c05fd5f1e/ADHM-13-0-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ad39/11582510/c35b14085197/ADHM-13-0-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ad39/11582510/8d1fecebdd74/ADHM-13-0-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ad39/11582510/f2001488f384/ADHM-13-0-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ad39/11582510/205fec64fb53/ADHM-13-0-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ad39/11582510/d4b4e3691313/ADHM-13-0-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ad39/11582510/7c4c05fd5f1e/ADHM-13-0-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ad39/11582510/c35b14085197/ADHM-13-0-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ad39/11582510/8d1fecebdd74/ADHM-13-0-g002.jpg
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