Spatiotemporal liposome-zwitterionic nano-hydrogel orchestrates immunomodulation and neurogenesis in spinal cord injury repair

Following spinal cord injury (SCI), the sequential dysregulation of the inflammatory microenvironment coupled with insufficient endogenous neuroregeneration severely impedes functional recovery. Conventional pharmacotherapies targeting singular pathological cascades and systemic drug administration fail to achieve comprehensive neural repair. Herein, an engineered liposome-zwitterionic nano-hydrogel drug delivery system (RA@Lip/Met-HSB) loaded with the novel neuromodulator retinoic acid (RA) and anti-inflammatory agent metformin (Met) was designed. This system enables temporally programmed release at the lesion site, leveraging the hierarchical degradation of the zwitterionic hydrogel and liposome. Mechanistically, this system orchestrates dual-phase therapeutic actions including acute-phase Met release drives microglial M2 polarization and attenuates neuronal apoptosis, while chronic-phase RA release promotes neural stem cells (NSCs) differentiation into functional neurons and oligodendrocytes, enhancing neuronal signal transmission efficiency via axonal remyelination. In murine SCI models, this system significantly restored motor function through: acute immunomodulation by reducing neuroinflammation and reduces apoptosis, thereby preserving endogenous NSCs, whereas chronic neural remodeling by boosting neurogenesis and facilitating remyelination, axonal regrowth and functional synapse formation. Collectively, this temporally programmed delivery strategy demonstrates robust spatiotemporal immunomodulation and neurogenesis, providing a transformative clinical rationale of the paradigm shift in SCI therapeutics for transitioning drug delivery from systemic to localized, and from temporally unordered to programmed drug administration.