Nano-crosslinked hydrogel facilitates sequential and synergistic luteolin/zinc therapy for enhanced spinal cord repair

The complex pathological progression of spinal cord injury (SCI) is characterized by spatiotemporal dynamics, thus requiring sequential and coordinated therapy that adapt to microenvironment. However, poor bioavailability and uncontrolled release of drugs always pose challenges for efficient recovery. This study proposes an integrated nanoparticle-hydrogel platform for sequential and synergetic delivery of the antioxidant luteolin (Lut) and the metal neuromodulator Zn²⁺. Polyphenol framework nanoparticles were prepared via a one-pot process using Zn²⁺ as a mediator to effectively deliver Lut. The nanoparticles functioned dually as efficient Lut carriers and as structural cross-linkers of an injectable hydrogel (Lut-Gel), which formed based on dual networks of dynamic covalent catechol-boronate crosslinking and ionic coordination, both mediated by the nanoparticles. The Lut-Gel exhibited microenvironment-responsive behaviors, enabling synergistic and sequentially controlled release of the antioxidant Lut and the neurogenesis modulator Zn²⁺. Under pH/ROS conditions, the cumulative Lut release increased from 29.4 ± 2.1% (physiological condition) to 85.1 ± 2.8%, concurrently, Zn²⁺ exhibited a gradual release profile devoid of burst kinetics. This benefits the mediation of the dynamic SCI pathology and simultaneously overcome the poor delivery efficiency of hydrophobic Lut and the toxicity risk of uncontrolled Zn²⁺ burst release. In a rat transection SCI model, Lut-Gel significantly attenuated early inflammatory and oxidative responses. The therapy elicited enhanced axonal regrowth and suppressed glial scar formation. A substantial number of axonal fibers undergo effective remodeling after injury, and the recovered neural tissue is accompanied by restored synaptic transmission functions. Compared with the SCI group, the BBB score of the Lut-Gel group reached 9.5, confirming significant functional recovery. Finally, the Lut-Gel, with nanoparticles anchored by covalent and ionic coordination dual dynamic networks, effectively promoted neural functional recovery. Collectively, this work establishes an adaptive therapeutic platform that integrates drug delivery with ion-mediated regulation. This strategy offers a promising approach for managing the complex pathophysiology of SCI and other neurological disorders.