Lipid Nanoparticle Delivery of Chemically Modified NGFR100W mRNA Alleviates Peripheral Neuropathy
Lipid Nanoparticle Delivery of Chemically Modified NGFR100W mRNA Alleviates Peripheral Neuropathy
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化学修饰的 NGFR100W mRNA 的脂质纳米颗粒递送可减轻周围神经病变
DOI：
10.1002/adhm.202202127
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发表时间：
2022-11-18
影响因子：
10
通讯作者：
Yang，Wen
中科院分区：
文献类型：
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作者：
Yu，Xiang;Yang，Zheng;Yang，Wen
信使RNA （mRNA）携带基因指令到细胞机制，以瞬时产生抗原或治疗性蛋白质，并在疫苗开发，癌症免疫治疗，蛋白质替代治疗和基因组工程中显示出巨大的潜力。本文描述了通过体外转录合成化学修饰的神经生长因子突变体（NGFR100W） mRNA。用Ig Kappa先导序列替换原始信号肽序列后，经密码子优化的NGFR100W mRNA高分泌成熟的NGFR100W，促进PC12细胞轴突生长。通过脂质纳米颗粒（LNP）递送N1 -甲基伪尿嘧啶修饰的mRNA， NGFR100W - mRNA - LNPs导致NGFR100W蛋白的成功表达，与NGFWT相比，NGFR100W蛋白显著降低了伤害性活性。这表明来源于外源性mRNA的NGFR100W引发了“无痛”的神经保护活性。此外，通过证明表皮内神经纤维的快速恢复，NGFR100W mRNA在紫杉醇诱导的周围神经病变模型中具有治疗价值。结果表明，体外转录的mRNA具有显著的序列设计灵活性和快速的靶蛋白体内功能验证。此外，研究结果强调了mRNA作为有益蛋白的补充，在预防或逆转一些慢性疾病（如周围神经病变）方面的治疗潜力。
Messenger RNA (mRNA) carries genetic instructions to the cell machinery for the transient production of antigens or therapeutic proteins and shows enormous potential in vaccine development, cancer immunotherapy, protein replacement therapy, and genome engineering. Here, the synthesis of chemically modified nerve growth factor mutant (NGFR100W) mRNA through in vitro transcription is described. After the replacement of the original signal peptide sequence with the Ig Kappa leader sequence, codon‐optimized NGFR100W mRNA yielded high secretion of mature NGFR100W, which promotes axon growth in PC12 cells. Using lipid nanoparticle (LNP)‐delivery of N1‐methylpseudouridine‐modified mRNA in mice, NGFR100W‐mRNA‐LNPs result in the successful expression of NGFR100W protein, which significantly reduces nociceptive activity compared to that of NGFWT. This indicates that NGFR100W derived from exogenous mRNA elicited “painless” neuroprotective activity. Additionally, the therapeutic value of NGFR100W mRNA is established in a paclitaxel‐induced peripheral neuropathy model by demonstrating the rapid recovery of intraepidermal nerve fibers. The results show that in vitro‐transcribed mRNA has significant flexibility in sequence design and fast in vivo functional validation of target proteins. Furthermore, the results highlight the therapeutic potential of mRNA as a supplement to beneficial proteins for preventing or reversing some chronic medical conditions, such as peripheral neuropathy.