Cited by 38RNA Interference and Gene DeliveryNerve injury and regenerationCancer Treatment and Pharmacology

Lipid Nanoparticle Delivery of Chemically Modified NGF R100W mRNA Alleviates Peripheral Neuropathy

Yu, Xiang, Yang, Zheng, Zhang, Yu, Xia, Jia, Zhang, Jiahui, Han, Qi, Yu, Hang, Wu, Chengbiao +3 more·2023·Advanced Healthcare Materials

Abstract

Abstract 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 (NGF R100W ) mRNA through in vitro transcription is described. After the replacement of the original signal peptide sequence with the Ig Kappa leader sequence, codon‐optimized NGF R100W mRNA yielded high secretion of mature NGF R100W , which promotes axon growth in PC12 cells. Using lipid nanoparticle (LNP)‐delivery of N1‐methylpseudouridine‐modified mRNA in mice, NGF R100W ‐mRNA‐LNPs result in the successful expression of NGF R100W protein, which significantly reduces nociceptive activity compared to that of NGF WT . This indicates that NGF R100W derived from exogenous mRNA elicited “painless” neuroprotective activity. Additionally, the therapeutic value of NGF R100W 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.

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Crossref · 10.1002/adhm.202202127

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  • AAV delivery in vivo may cause accumulation of off-target mutations.

    “| Delivery methods improvement | Application in vivo [95–105] | AAV: Last for years in terminally differentiated cell types | May cause accumulation of off-target mutations |”

    From Off-target effects in CRISPR/Cas9 gene editing (2023) · cites this paper as [100]

  • LNP delivery in vivo can be quickly degraded.

    “| Delivery methods improvement | Application in vivo [95–105] | LNP: Can be quickly degraded in vivo | Eliminate off-target effects |”

    From Off-target effects in CRISPR/Cas9 gene editing (2023) · cites this paper as [100]

  • AAV delivery in vivo lasts for years in terminally differentiated cell types.

    “| Delivery methods improvement | Application in vivo [95–105] | AAV: Last for years in terminally differentiated cell types | May cause accumulation of off-target mutations |”

    From Off-target effects in CRISPR/Cas9 gene editing (2023) · cites this paper as [100]

  • LNP delivery in vivo eliminates off-target effects.

    “| Delivery methods improvement | Application in vivo [95–105] | LNP: Can be quickly degraded in vivo | Eliminate off-target effects |”

    From Off-target effects in CRISPR/Cas9 gene editing (2023) · cites this paper as [100]

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Authors
Yu, X., Yang, Z., Zhang, Y., Xia, J., Zhang, J., Han, Q., Yu, H., Wu, C., Xu, Y., Xu, W., & Yang, W.
Affiliations
  • Shanghai Jiao Tong University (CN)
  • Shanghai RNACure Biopharma Co., Ltd. Shanghai 200438 P. R. China
  • University of California San Diego (US)
Corresponding author
  • Xu, Yingjie
  • Xu, Wei
  • Yang, Wen
Venue
Advanced Healthcare Materials
Publisher
Wiley
Published
2022-11-18
Volume
12
Issue
3
Pages
e2202127-e2202127
ISSN
  • 2192-2640 (ISSN-L)
  • 2192-2659
OpenAlex
W4308060847
Cited by
38
References
52
Citations by year
2026: 8 · 2025: 12 · 2024: 12 · 2023: 6
FWCI
2.45
Type
journal article
Language
en
Open access
closed
Locations
  • Advanced Healthcare Materials (publishedVersion)
  • PubMed (publishedVersion)
Funders
National Natural Science Foundation of China (81600920, 31871430, 31900856)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Nerve injury and regeneration
  • Health Sciences › Medicine › Oncology › Cancer Treatment and Pharmacology
Keywords
mRNA therapeutics, lipid nanoparticle delivery, peripheral neuropathy, paclitaxel-induced peripheral neuropathy, N1-methylpseudouridine, codon optimization, in vitro transcription, axon growth, PC12 cells, nociception, neuroprotection, intraepidermal nerve fibers
MeSH terms
Animals, Liposomes, Peripheral Nervous System Diseases, RNA, Messenger, Nerve Growth Factor, Mice, Rats, Nanoparticles

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