Nanoparticle-Assembled Multifaceted Hydrogel Therapy Promotes Functional Recovery After Spinal Cord Injury

Spinal cord injury (SCI) is a devastating neuropathological condition. Currently, there is an urgent need for highly effective therapies for SCI treatment. Here we developed a multifunctional hydrogel therapy (LPPXN), by rationally integrating pharmacologically active nanomicelles into hydrogels composed of noncovalently cross-linked nanoparticles that are self-assembled by a functionalized amphiphilic triblock polymer. LPPXN exhibits temperature-responsive gelation, high strength, favorable bioadhesive properties, and excellent shear-thinning and self-healing capabilities under pathological conditions. Following local injection, LPPXN can be sustained for over one month. Therapeutically, LPPXN significantly improved the structural integrity of injured spinal cords and promoted function recovery in a mouse model of SCI. Furthermore, LPPXN demonstrated beneficial therapeutic effects in mice with SCI combined with ischemia-reperfusion injury, a model closely replicating real-world scenarios. Mechanistically, LPPXN treatment promoted neuroprotective astrocyte polarization and structured network assembly at the SCI lesion site, while reconstructing a regenerative niche to enhance neural preservation and protection. This multifaceted efficacy was primarily mediated through suppressing oxidative/inflammatory cascades, inducing anti-inflammatory polarization of macrophages and microglia, and modulating the CCL2/CCL5-JAK-STAT signaling pathway. Notably, LPPXN showed excellent tissue biocompatibility in the spinal cord. Accordingly, LPPXN warrants further development as a promising therapeutic option for SCI and other nerve injury-associated diseases.