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<p>Central nervous system (CNS) injury is a leading cause of death and long-term disability worldwide. Neurological deficits reflect disruption of central neural circuits. A major barrier to circuit repair is the intrinsically low regenerative potential of adult CNS neurons—linked in part to failure of injury-induced nuclear export of class IIa histone deacetylases (notably HDAC5)—together with a hostile post-injury microenvironment. Here we present a multifunctional nanosystem, encapsulating the class IIa HDAC4/5-selective inhibitor LMK-235 and featuring an electroactive polyaniline coating with asymmetrically distributed 5-hydroxytryptamine moieties. Upon reaching the lesion, our nanosystem assembles into large-pore scaffolds that (i) inhibit the activity of nuclear-retained class IIa HDACs in neurons and thereby reactivate intrinsic regenerative programs, (ii) regulate microglial activation to mitigate neuroinflammation, and (iii) provide an electroactive interface promoting activity-dependent synaptic reconnection. This multi-pronged approach illustrates an integrated platform with translational potential for CNS disorders in which circuit disconnection constrains recovery.</p>

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Self-assembling scaffolds epigenetically reactivate and electroactively guide neuronal regeneration to restore central neural circuits

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年5月4日

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  • Shiqiang Tong,
  • Shuai Ye,
  • Fenfen Ma,
  • Xiaoying Xie,
  • Yinzhe Sun,
  • Chuchu Ma,
  • Tiantian Shi,
  • Zheng Cheng,
  • Chang Li,
  • Weili Han,
  • Laozhi Xie,
  • Songlei Zhou,
  • Jianing Gong,
  • Chen Huang,
  • Yukun Huang,
  • Gan Jiang,
  • Xiaolin Liu,
  • Bing Li,
  • Feng Zeng,
  • Jingru Gong,
  • Zhihua Wang,
  • Xiaoling Gao,
  • Qiyong Mei,
  • Wei-Guang Li,
  • Jun Chen

摘要

Central nervous system (CNS) injury is a leading cause of death and long-term disability worldwide. Neurological deficits reflect disruption of central neural circuits. A major barrier to circuit repair is the intrinsically low regenerative potential of adult CNS neurons—linked in part to failure of injury-induced nuclear export of class IIa histone deacetylases (notably HDAC5)—together with a hostile post-injury microenvironment. Here we present a multifunctional nanosystem, encapsulating the class IIa HDAC4/5-selective inhibitor LMK-235 and featuring an electroactive polyaniline coating with asymmetrically distributed 5-hydroxytryptamine moieties. Upon reaching the lesion, our nanosystem assembles into large-pore scaffolds that (i) inhibit the activity of nuclear-retained class IIa HDACs in neurons and thereby reactivate intrinsic regenerative programs, (ii) regulate microglial activation to mitigate neuroinflammation, and (iii) provide an electroactive interface promoting activity-dependent synaptic reconnection. This multi-pronged approach illustrates an integrated platform with translational potential for CNS disorders in which circuit disconnection constrains recovery.