Serotonergic System‐Targeted Nucleic Acid Hydrogel Coordinates Excitability Restoration and Circuit Reconstruction for Spinal Cord Injury Therapy
Source abstract
Abstract
ABSTRACT Despite the persistence of spared spinal circuits capable of relaying commands after spinal cord injury (SCI), their contribution to recovery remains constrained by functional dormancy of spared neurons and impaired reconnection across the lesion. Serotonergic neuromodulation is pivotal for reactivating dormant neurons, however, achieving precise targeting and modulation of the serotonergic system poses translational challenges. Here, a DNA/RNA heteroduplex hydrogel is reported that integrates 5‐hydroxytryptamine (5‐HT)‐mediated neuronal excitability restoration with phosphatase and tensin homolog (PTEN)‐targeted spinal circuit reconstruction for SCI therapy. The 5‐hydroxytryptophan (5‐HTP)‐derived motif, serving both as a targeting ligand and as a neuromodulator, is site‐specifically grafted onto three phosphorothioate‐bearing single‐stranded DNA (ssDNA) strands, which self‐assemble into Y‐shaped motifs and are subsequently crosslinked by sticky‐ended PTEN small interfering RNA (siRNA) to form the hydrogel network. After lesion‐site administration, the hydrogel undergoes DNase‐mediated network disassembly into nanogels that exert two complementary therapeutic actions by targeting serotonergic system: restoring excitability to reactivate dormant interneurons and reconstructing descending connectivity to reintegrate spared circuits with the host spinal cord, thereby restoring sensory and locomotor functions in paralyzed mice. This strategy coordinately reinstates functional excitability and structural rebuilding by engaging multiple interlocking mechanisms, advancing a versatile paradigm for integrative therapy of central nervous system (CNS) disorders.
Source: crossref · Quality: baseline
Research context
OpenAlex topics: Nerve injury and regeneration · Spinal Cord Injury Research · Neurogenetic and Muscular Disorders Research
SciVX discovery tags are terminology-based. OpenAlex topics are source-provided classifications.
Affiliations
Department of Orthopaedics, Qilu Hospital of Shandong University, Shandong University Centre for Orthopaedics, Advanced Medical Research Institute, Cheeloo College of Medicine Shandong University Jinan Shandong P. R. China
School of Chemistry and Chemical Engineering, Frontiers Science Center for Transformative Molecules, Shanghai Key Laboratory for Molecular Engineering of Chiral Drugs Shanghai Jiao Tong University 800 Dongchuan Road Shanghai P. R. China
Department of Ophthalmology, Eye & ENT Hospital, State Key Laboratory of Brain Function and Disorders Fudan University Shanghai P. R. China
Department of Liver Surgery and Transplantation and Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Liver Cancer Institute Zhongshan Hospital Fudan University Shanghai P. R. China
Department of Geriatric Medicine Qilu Hospital of Shandong University Wenhuaxi Road 107 Jinan Shandong P. R. China
Department of Orthopaedics, The Second Qilu Hospital of Shandong University, Cheeloo College of Medicine Shandong University Jinan Shandong P. R. China
Institute of Molecular Medicine, Shanghai Jiao Tong University Affiliated Renji Hospital Shanghai Jiao Tong University School of Medicine Shanghai P. R. China
Department of Orthopaedics, Tianjin Medical University General Hospital, Tianjin Medical University International Science and Technology Cooperation Base of Spinal Cord Injury Tianjin Key Laboratory of Spine and Spinal Cord Tianjin P. R. China
Funding
National Natural Science Foundation of China · China Postdoctoral Science Foundation
References (98)
Show source-provided references
1. 10.1038/s41593-022-01196-110.1038/s41593-022-01196-1 ↗
2. 10.1038/s41392-023-01477-610.1038/s41392-023-01477-6 ↗
3. 10.1172/JCI9060810.1172/JCI90608 ↗
4. 10.1126/science.adi641210.1126/science.adi6412 ↗
5. 10.1016/j.cell.2018.06.00510.1016/j.cell.2018.06.005 ↗
6. 10.1038/s41580-022-00562-y10.1038/s41580-022-00562-y ↗
7. 10.1016/S0140-6736(11)60547-310.1016/S0140-6736(11)60547-3 ↗
8. 10.1038/s41565-023-01416-010.1038/s41565-023-01416-0 ↗
9. 10.1038/s41586-018-0467-610.1038/s41586-018-0467-6 ↗
10. 10.1038/nn.260310.1038/nn.2603 ↗
11. 10.1038/nrdp.2017.1810.1038/nrdp.2017.18 ↗
12. 10.1038/s41467-024-44898-910.1038/s41467-024-44898-9 ↗
13. 10.1038/s41586-023-06094-510.1038/s41586-023-06094-5 ↗
14. 10.1152/physrev.00015.201910.1152/physrev.00015.2019 ↗
15. 10.1038/nrn260810.1038/nrn2608 ↗
16. 10.1146/annurev.neuro.29.051605.11291010.1146/annurev.neuro.29.051605.112910 ↗
17. 10.1038/nm.216010.1038/nm.2160 ↗
18. 10.3389/fncir.2014.0015110.3389/fncir.2014.00151 ↗
19. 10.3389/fncir.2020.0001410.3389/fncir.2020.00014 ↗
20. 10.1038/s41467-021-27419-w10.1038/s41467-021-27419-w ↗
21. 10.1038/s41593-022-01186-310.1038/s41593-022-01186-3 ↗
22. 10.1038/s41593-022-01213-310.1038/s41593-022-01213-3 ↗
23. 10.1016/j.brainres.2005.10.07510.1016/j.brainres.2005.10.075 ↗
24. 10.1146/annurev.neuro.27.070203.14420610.1146/annurev.neuro.27.070203.144206 ↗
25. 10.1016/S0031-6997(24)01478-910.1016/S0031-6997(24)01478-9 ↗
26. 10.1038/s41583-020-0314-210.1038/s41583-020-0314-2 ↗
27. 10.1155/2018/423270610.1155/2018/4232706 ↗
28. 10.1126/sciadv.ads493810.1126/sciadv.ads4938 ↗
29. 10.1038/s41467-020-20703-110.1038/s41467-020-20703-1 ↗
30. 10.1002/adma.20250540210.1002/adma.202505402 ↗
31. 10.1126/science.121741610.1126/science.1217416 ↗
32. 10.1016/j.cell.2014.11.01910.1016/j.cell.2014.11.019 ↗
33. 10.1016/S1474-4422(21)00464-610.1016/S1474-4422(21)00464-6 ↗
34. 10.1016/j.cell.2021.10.02910.1016/j.cell.2021.10.029 ↗
35. 10.1126/science.116156610.1126/science.1161566 ↗
36. 10.1038/s41392-022-00885-410.1038/s41392-022-00885-4 ↗
37. 10.1073/pnas.150144111210.1073/pnas.1501441112 ↗
38. 10.1186/s13287-021-02668-010.1186/s13287-021-02668-0 ↗
39. 10.1002/adma.20230811010.1002/adma.202308110 ↗
40. 10.1038/s41392-023-01589-z10.1038/s41392-023-01589-z ↗
41. 10.1126/science.aau015910.1126/science.aau0159 ↗
42. 10.1021/acs.jcim.2c0044110.1021/acs.jcim.2c00441 ↗
43. 10.1038/s41573-021-00162-z10.1038/s41573-021-00162-z ↗
44. 10.1038/s41573-019-0017-410.1038/s41573-019-0017-4 ↗
45. 10.1146/annurev-neuro-070918-05050110.1146/annurev-neuro-070918-050501 ↗
46. 10.1146/annurev-pharmtox-010919-02373810.1146/annurev-pharmtox-010919-023738 ↗
47. 10.15252/emmm.20201324310.15252/emmm.202013243 ↗
48. 10.1038/s41573-020-0075-710.1038/s41573-020-0075-7 ↗
49. 10.1038/s41576-021-00439-410.1038/s41576-021-00439-4 ↗
50. 10.3389/fnagi.2019.0037310.3389/fnagi.2019.00373 ↗
51. Enhanced delivery of antibodies across the blood‐brain barrier via TEMs with inherent receptor‐mediated phagocytosis
52. 10.1016/j.it.2007.07.01110.1016/j.it.2007.07.011 ↗
53. 10.1016/j.addr.2020.04.01210.1016/j.addr.2020.04.012 ↗
54. 10.1038/nrd.2016.19910.1038/nrd.2016.199 ↗
55. 10.1126/sciadv.abb442910.1126/sciadv.abb4429 ↗
56. 10.1126/sciadv.abn294110.1126/sciadv.abn2941 ↗
57. 10.1021/cn100020510.1021/cn1000205 ↗
58. 10.1002/advs.20230624810.1002/advs.202306248 ↗
59. 10.1038/s41593-022-01067-910.1038/s41593-022-01067-9 ↗
60. 10.1016/j.cmet.2023.06.00410.1016/j.cmet.2023.06.004 ↗
61. 10.1016/j.immuni.2013.02.01210.1016/j.immuni.2013.02.012 ↗
62. 10.1002/adma.20241162810.1002/adma.202411628 ↗
63. 10.1038/s41467-023-36587-w10.1038/s41467-023-36587-w ↗
64. 10.1038/cddis.2011.9810.1038/cddis.2011.98 ↗
65. 10.1093/nar/gkae10010.1093/nar/gkae100 ↗
66. 10.1038/s41392-020-0207-x10.1038/s41392-020-0207-x ↗
67. 10.1038/416636a10.1038/416636a ↗
68. 10.1002/advs.20230930510.1002/advs.202309305 ↗
69. 10.1002/adma.20230762410.1002/adma.202307624 ↗
70. 10.1002/adma.20250279510.1002/adma.202502795 ↗
71. 10.1016/j.ymthe.2019.09.00410.1016/j.ymthe.2019.09.004 ↗
72. 10.1038/s41467-022-31797-010.1038/s41467-022-31797-0 ↗
73. 10.1038/s41586-020-2795-610.1038/s41586-020-2795-6 ↗
74. 10.1038/s41419-019-1802-z10.1038/s41419-019-1802-z ↗
75. 10.1016/S1474-4422(24)00173-X10.1016/S1474-4422(24)00173-X ↗
76. 10.13004/kjnt.2022.18.e2110.13004/kjnt.2022.18.e21 ↗
77. 10.1089/neu.2015.419210.1089/neu.2015.4192 ↗
78. 10.1038/s41467-024-50564-x10.1038/s41467-024-50564-x ↗
79. 10.1038/nature1397410.1038/nature13974 ↗
80. 10.1038/nrn132610.1038/nrn1326 ↗
81. 10.1016/j.cell.2012.08.02010.1016/j.cell.2012.08.020 ↗
82. 10.1016/j.stem.2020.07.00710.1016/j.stem.2020.07.007 ↗
83. 10.1038/nn.248210.1038/nn.2482 ↗
84. 10.1016/S0361-9230(00)00402-010.1016/S0361-9230(00)00402-0 ↗
85. 10.1172/JCI9783710.1172/JCI97837 ↗
86. 10.1126/sciadv.ado912010.1126/sciadv.ado9120 ↗
87. 10.4103/1673-5374.35576310.4103/1673-5374.355763 ↗
88. 10.3390/app1109409710.3390/app11094097 ↗
89. 10.1186/s40634-017-0105-510.1186/s40634-017-0105-5 ↗
90. 10.1146/annurev-neuro-083122-02532510.1146/annurev-neuro-083122-025325 ↗
91. 10.1038/s41467-020-19914-310.1038/s41467-020-19914-3 ↗
92. 10.1038/nrn.2016.910.1038/nrn.2016.9 ↗
93. 10.1002/jcc.2125610.1002/jcc.21256 ↗
94. 10.1021/acs.jcim.1c0020310.1021/acs.jcim.1c00203 ↗
95. 10.1002/jcc.2133410.1002/jcc.21334 ↗
96. 10.1152/physiol.00042.200810.1152/physiol.00042.2008 ↗
97. 10.1002/advs.20220452810.1002/advs.202204528 ↗
98. A. E.Ropper D. K.Thakor andI.Han “Defining recovery neurobiology of injured spinal cord by synthetic matrix‐assisted hMSC implantation ” inProceedings of the National Academy of Sciences of the United States of America(2017) E820–E829.10.1073/pnas.1616340114 ↗