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Background <p>Traumatic optic neuropathy (TON) is a devastating cause of irreversible vision loss for which no effective treatment currently exists. Its poor prognosis stems from two major challenges: the limited regenerative capacity of retinal ganglion cells (RGCs) and the hostile, inflammation-driven environment that follows injury.</p> Results <p>In this work, using transcriptomic bioinformatic and histopathological analysis, we discovered that mechanical trauma and subsequent neuroinflammation trigger microglial pyroptosis through the NLRP3/CASP1/GSDMD pathway. This process amplifies inflammatory cascades and exacerbates RGC degeneration via microglia-neuron interactions. To overcome these dual barriers, we engineered a microglia-targeted lipid nanoparticle (LNP) platform co-delivering disulfiram (DSF), a selective GSDMD inhibitor, together with self-amplifying mRNA (saRNA) encoding ciliary neurotrophic factor (CNTF). We found that this combinatorial strategy concurrently suppresses pyroptosis-driven neuroinflammation while providing sustained neurotrophic support. Through comprehensive in vitro and in vivo evaluations, the co-delivery system showed enhanced RGC survival, remarkable axonal regeneration, and eventually significant restoration of visual function.</p> Conclusions <p>In summary, our results demonstrate that a coordinated strategy targeting both neuroinflammatory mechanisms and regenerative pathways yields superior therapeutic outcomes in TON. This work underscores the potential of integrated RNA-small molecule therapies as a promising multi-target treatment paradigm, with broad applicability for other neuroinflammatory and neurodegenerative diseases.</p> Graphical abstract <p></p>

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Self-amplifying RNA therapy encoding CNTF with disulfiram co-delivery promotes optic nerve repair through microglial pyroptosis inhibition and RGC axonal regeneration

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年3月13日

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  • Qianyue Zhang,
  • Yusha Liu,
  • Qin Wei,
  • Mingyang Song,
  • Siwei Liu,
  • Haiyang Zhang,
  • Tingyu Deng,
  • Chutong Zhang,
  • Kexin Tan,
  • Rui Huang,
  • Ni Ni,
  • Jun Zhang,
  • Ping Gu,
  • Gang Du,
  • Jipeng Li,
  • Yingzhi Chen,
  • Huifang Zhou,
  • Xianqun Fan

摘要

Background

Traumatic optic neuropathy (TON) is a devastating cause of irreversible vision loss for which no effective treatment currently exists. Its poor prognosis stems from two major challenges: the limited regenerative capacity of retinal ganglion cells (RGCs) and the hostile, inflammation-driven environment that follows injury.

Results

In this work, using transcriptomic bioinformatic and histopathological analysis, we discovered that mechanical trauma and subsequent neuroinflammation trigger microglial pyroptosis through the NLRP3/CASP1/GSDMD pathway. This process amplifies inflammatory cascades and exacerbates RGC degeneration via microglia-neuron interactions. To overcome these dual barriers, we engineered a microglia-targeted lipid nanoparticle (LNP) platform co-delivering disulfiram (DSF), a selective GSDMD inhibitor, together with self-amplifying mRNA (saRNA) encoding ciliary neurotrophic factor (CNTF). We found that this combinatorial strategy concurrently suppresses pyroptosis-driven neuroinflammation while providing sustained neurotrophic support. Through comprehensive in vitro and in vivo evaluations, the co-delivery system showed enhanced RGC survival, remarkable axonal regeneration, and eventually significant restoration of visual function.

Conclusions

In summary, our results demonstrate that a coordinated strategy targeting both neuroinflammatory mechanisms and regenerative pathways yields superior therapeutic outcomes in TON. This work underscores the potential of integrated RNA-small molecule therapies as a promising multi-target treatment paradigm, with broad applicability for other neuroinflammatory and neurodegenerative diseases.

Graphical abstract