Serotonergic System‐Targeted Nucleic Acid Hydrogel Coordinates Excitability Restoration and Circuit Reconstruction for Spinal Cord Injury Therapy

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.