Serotonergic System‐Targeted Nucleic Acid Hydrogel Coordinates Excitability Restoration and Circuit Reconstruction for Spinal Cord Injury Therapy
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.
Article Details
Authors (20)
Chunlin Li
Key Laboratory of Advanced Catalysis, Gansu Province; State Key Laboratory of Natural Product Chemistry, College of Chemistry and Chemical Engineering
Xiaoqing Zhao
Kai Jiang
Department of Pharmacy, The First Affiliated Hospital of the University of Science and Technology of China, and State Key Laboratory of Precision and Intelligent Chemistry
Haixia Kang
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
Shuo Liu
Linlin Jiang
Baoshuai Bai
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
Haonan Cui
Ziyang Zhang
Menglei Dong
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
Ruizhi Zhang
Chenbo Zou
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
Shenghui Shang
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
Chi Zhang
Xiangchuang Fan
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
Lijuan Zhu
Institute of Photochemistry and Photofunctional Materials, School of Materials and Chemistry
Huiquan Duan
Chuan Zhang
Shiqing Feng
Hengxing Zhou
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