Human BMP4 mRNA Encapsulated in Lipid Nanoparticle Delayed Cartilage Degeneration but Has a Limited Enhancement Effect on Bone Healing in Aged Mice
人骨形态发生蛋白4 mRNA包裹于脂质纳米颗粒中可延缓老年小鼠软骨退化，但对骨愈合的促进作用有限。
Xueqin Gao, Zuokui Xiao, Matthieu Huard, Keisuke Nakayama, Aryn Cummmins, Britney Force, Hongye Li, Chiara Mancino, John Cooke, Francesca Taraballi, Marc Philippon, Johnny Huard (2026) Human BMP4 mRNA Encapsulated in Lipid Nanoparticle Delayed Cartilage Degeneration but Has a Limited Enhancement Effect on Bone Healing in Aged Mice Preprints.org
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Abstract
Segmental bone defects and age-related osteoarthritis (OA) are clinically challenging in terms of treatment. Although preclinical studies have demonstrated efficacy for bone defect healing and OA using ex vivo gene therapy or biomaterial sustain-release delivery, few have translated into clinical therapies due to safety concerns. Bone morphogenetic proteins belong to the TGFβ superfamily and are effective in bone and cartilage regeneration/repair. Among BMPs, BMP4 is not only effective in promoting bone and cartilage repair but also promotes stem cell renewal potential and exhibits anti-aging effects. Therefore, the aim of this study is to investigate whether human BMP4 mRNA encapsulated in lipid nanoparticles (hBMP4/LNP) can promote bone and cartilage repair. Our results demonstrated that hBMP4/LNP promoted limited new bone formation only at 2 weeks after creation of defect in critical-sized calvarial bone defect in aged mice at 50µg dose when delivered using fibrin sealant hydrogel as revealed by micro-CT and histology. However, intra-articular injection (IA) of lower doses (2.5 and 5µg) in aged mice knee joints prevented cartilage loss as demonstrated by micro-CT, decreased OARSI histology scores and improved cartilage specific matrix COL2. HBMP4/LNP treatment showed a trend of pain alleviation and did not change serum hyaluronic acid levels. In conclusion, human BMP4 mRNA encapsulated in lipid nanoparticle improved cartilage repair & delay cartilage degeneration in age mice while having a limited effect on bone healing, even a higher dosage. These results suggest that hBMP4 mRNA encapsulated with lipid nanoparticle represents a promising treatment for age-related OA.
节段性骨缺损和年龄相关性骨关节炎（OA）的治疗在临床上极具挑战性。尽管临床前研究已证实，体外基因治疗或生物材料缓释递送在促进骨缺损愈合和治疗OA方面具有疗效，但由于安全性问题，鲜有疗法转化为临床应用。骨形态发生蛋白（BMP）属于TGFβ超家族，在骨和软骨再生/修复中发挥重要作用。在众多BMP中，BMP4不仅能有效促进骨和软骨修复，还能促进干细胞更新，并具有抗衰老作用。因此，本研究旨在探讨人BMP4 mRNA包裹于脂质纳米颗粒（hBMP4/LNP）是否能够促进骨和软骨修复。我们的研究结果表明，在老年小鼠颅骨临界尺寸骨缺损模型中，使用纤维蛋白密封剂水凝胶递送50µg剂量的hBMP4/LNP，仅在缺损形成两周后才能促进有限的新骨形成，这一结果通过微型CT和组织学分析得以证实。然而，在老年小鼠膝关节内注射较低剂量（2.5和5µg）的HBMP4/LNP可预防软骨丢失（微型CT扫描证实），降低OARSI组织学评分，并改善软骨特异性基质COL2的含量。HBMP4/LNP治疗显示出缓解疼痛的趋势，但并未改变血清透明质酸水平。总之，脂质纳米颗粒包裹的人BMP4 mRNA可改善老年小鼠的软骨修复并延缓软骨退变，即使剂量较高，对骨愈合的影响也有限。这些结果表明，脂质纳米颗粒包裹的hBMP4 mRNA有望成为治疗老年骨关节炎的一种有效方法。
Links
https://doi.org/10.20944/preprints202604.0770.v1http://dx.doi.org/10.20944/preprints202604.0770.v1
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