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

Overview

Authors: Shiqiang Tong^1,2, Shuai Ye^3,4, Fenfen Ma^1,5, Xiaoying Xie¹, Yinzhe Sun¹, Chuchu Ma¹, Tiantian Shi³, Zheng Cheng¹, Chang Li¹, Weili Han⁶, Laozhi Xie¹, Songlei Zhou¹, Jianing Gong¹, Chen Huang⁷, Yukun Huang⁸, Gan Jiang⁸, Xiaolin Liu⁵, Bing Li⁴, Feng Zeng⁹, Jingru Gong⁵, Zhihua Wang¹⁰, Xiaoling Gao⁸, Qiyong Mei⁹, Wei-Guang Li^3,4,11, Jun Chen¹

ORCID iDs: Shuai Ye, Jianing Gong, Yukun Huang, Gan Jiang, Xiaoling Gao, Wei-Guang Li, Jun Chen

Institutions: Pudong Medical Center (China); China Pharmaceutical University (China); Fudan University (China); Shanghai University (China); Shanghai Jiao Tong University (China); Second Military Medical University (China)

Journal: Nature communications, volume 17, issue 1, article 5987

Dates: received 12 June 2025; accepted 30 March 2026; published online 4 May 2026

Type: Research article · Language: English

License: CC BY

Identifiers: DOI 10.1038/s41467-026-72397-6 · PMID 42082500 · PMCID PMC13347008 · OpenAlex W7160052177

Open access: gold, a free copy (OpenAlex)

Status: data only

Categories: mouse (organism)

Methods: Statistics, Machine learning

Keywords: Nanoparticles, Drug delivery

MeSH: Epigenesis, Genetic*, Nerve Regeneration*, Neurons*, Tissue Scaffolds*, Animals, Histone Deacetylase Inhibitors, Histone Deacetylases, Mice, Microglia (* major topic)

Topic: Histone Deacetylase Inhibitors Research (Molecular Biology, Biochemistry, Genetics and Molecular Biology), according to OpenAlex

Funding: National Natural Science Foundation of China (National Science Foundation of China) (82373814, 32201170, 82473850, 82471324); 1. Programs of Medical Engineering fund of Fudan University (Grant Reference Number: yg2023-24); 1. Key Discipline Construction Project of Pudong Health Bureau of Shanghai: Clinical Pharmacy (Grant Reference Number: PWZxk2022-27) 2. Clinical Pharmacy Key Specialized subject Construction Project of Pudong Hospital affiliated to Fudan University (Grant Reference Number: Tszk2020-05); 1. Science and Technology Development Fund of Shanghai Pudong New Area (Grant Reference Number: PKJ2024-Y51) 2. The Medical Discipline Construction Program of Shanghai Pudong New Area Health Commission (the Key Disciplines Program,Grant Reference Number: PWZxk2025-09); Shanghai Science and Technology Development Foundation (Shanghai Science and Technology Development Fund) (23S41900100); 1. Innovation Program of Shanghai Municipal Education Commission (Grant Reference Number: 2023ZKZD21); 1. Programs of Shanghai Academic/Technology Research Leader (Grant Reference Number: 22XD1420700)

Citations: not cited yet (Europe PMC); 106 references in the paper

Abstract

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.

Reproduced under the paper's license (CC BY), from the paper cited above.

Code

The paper links to its data, not to its authors' code: see the Data section.

The paper's code and data availability statement is in the Data section.

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Data

Datasets cited

iprox.cn/page/home.html, at iprox.cn; found in “Data availability”

Data availability

The proteomics raw data generated in this study have been deposited in the ProteomeXchange Consortium via the iProX partner repository under accession code PXD051033 [https://www.iprox.cn/page/home.html]. Other data generated in this study are provided in the Supplementary Information/Source Data file. Any additional requests for information can be directed to, and will be fulfilled by, the corresponding authors. Source data are provided with this paper.

Reproduced under the paper's license (CC BY), from the paper cited above.

Versions

The history of this record: each version stored by the harvester or made by a correction of its authors or of the maintainers of its code, and what changed in its facts. The texts of the paper (its abstract, its availability statements) are not part of it; versions that changed only those are not listed.

Version 1, 28 September 2026: the first record

Recorded: type, language, journal, volume, issue, pages, dates, 25 authors, 2 keywords, 9 MeSH terms, 7 funders, 105 references.

Cite

This paper

Tong, S., Ye, S., Ma, F., Xie, X., Sun, Y., Ma, C., Shi, T., Cheng, Z., Li, C., Han, W., Xie, L., Zhou, S., Gong, J., Huang, C., Huang, Y., Jiang, G., Liu, X., Li, B., Zeng, F., . . . Chen, J. (2026). Self-assembling scaffolds epigenetically reactivate and electroactively guide neuronal regeneration to restore central neural circuits. Nature communications, 17(1), 5987. https://doi.org/10.1038/s41467-026-72397-6

BibTeX

@article{tong2026self, author = {Tong, Shiqiang and Ye, Shuai and Ma, Fenfen and Xie, Xiaoying and Sun, Yinzhe and Ma, Chuchu and Shi, Tiantian and Cheng, Zheng and Li, Chang and Han, Weili and Xie, Laozhi and Zhou, Songlei and Gong, Jianing and Huang, Chen and Huang, Yukun and Jiang, Gan and Liu, Xiaolin and Li, Bing and Zeng, Feng and Gong, Jingru and Wang, Zhihua and Gao, Xiaoling and Mei, Qiyong and Li, Wei-Guang and Chen, Jun}, title = {{Self-assembling scaffolds epigenetically reactivate and electroactively guide neuronal regeneration to restore central neural circuits}}, journal = {Nature communications}, year = {2026}, month = may, volume = {17}, number = {1}, pages = {5987}, publisher = {Nature Publishing Group}, issn = {2041-1723}, doi = {10.1038/s41467-026-72397-6}, url = {https://doi.org/10.1038/s41467-026-72397-6}, pmid = {42082500}, pmcid = {PMC13347008} }

RIS

TY - JOUR AU - Tong, Shiqiang AU - Ye, Shuai AU - Ma, Fenfen AU - Xie, Xiaoying AU - Sun, Yinzhe AU - Ma, Chuchu AU - Shi, Tiantian AU - Cheng, Zheng AU - Li, Chang AU - Han, Weili AU - Xie, Laozhi AU - Zhou, Songlei AU - Gong, Jianing AU - Huang, Chen AU - Huang, Yukun AU - Jiang, Gan AU - Liu, Xiaolin AU - Li, Bing AU - Zeng, Feng AU - Gong, Jingru AU - Wang, Zhihua AU - Gao, Xiaoling AU - Mei, Qiyong AU - Li, Wei-Guang AU - Chen, Jun TI - Self-assembling scaffolds epigenetically reactivate and electroactively guide neuronal regeneration to restore central neural circuits T2 - Nature communications J2 - Nat Commun PY - 2026 DA - 2026/05/04 VL - 17 IS - 1 SP - 5987 SN - 2041-1723 PB - Nature Publishing Group DO - 10.1038/s41467-026-72397-6 UR - https://doi.org/10.1038/s41467-026-72397-6 LA - en ER -

CSL-JSON

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