Although spinal cord injury (SCI) still retains spinal cord circuits capable of transmitting instructions, the contribution to recovery is still limited by the functional dormancy of surviving neurons and the restricted reconnection between lesions. Serotonergic neuromodulation is crucial for reactivating dormant neurons, yet achieving the precise localization and regulation of the serotonergic system still presents translational challenges. This article reports a DNA/RNA heteroduplex hydrogel that combines 5-hydroxytryptamine (5-HT)-mediated neuronal excitability recovery with phosphatase and tensin homolog (PTEN)-targeted spinal cord circuit reconstruction for spinal cord injury treatment. Derived from the 5-hydroxytryptophan (5-HTP) motif, it acts as both a targeting ligand and a neuroregulatory factor, being specifically linked to three phosphosulfate-containing single-stranded DNA (ssDNA) strands. These strands self-assemble into a Y-shaped motif and subsequently cross-link through the sticky ends of PTEN small interfering RNA (siRNA) to form a hydrogel network. After administration to the lesion site, the hydrogel is disassembled into nanogels by DNase-mediated network dissolution, achieving two complementary therapeutic effects: restoring excitability to re-activate dormant intermediate neurons and reconstructing descending connections to re-integrate the remaining circuits with the host spinal cord, thereby restoring sensory and motor functions in paralyzed mice. This strategy synergistically restores functional excitability and structural reconstruction through multiple interlocking mechanisms, promoting the diversification of comprehensive treatment paradigms in the central nervous system (CNS). This research was published in Advanced Materials under the title "Serotonergic System-Targeted Nucleic Acid Hydrogel Coordinates Excitability Restoration and Circuit Reconstruction for Spinal Cord Injury Therapy".
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DOI: 10.1002/adma.202521427