A Chronologically Programmed Core–Shell Microneedle Patch for Staged Therapy of Spinal Cord Injury

Secondary injury following spinal cord injury (SCI) is not a unidimensional pathological process; rather, it involves a spatiotemporally organized cascade that rapidly evolves from an acute inflammatory storm and tissue breakdown to stalled repair and impaired regeneration in the subacute phase. However, most current therapeutic strategies depend on single-dose administration or isolated targets and thus fail to keep pace with the dynamic progression of SCI. Here, we developed a core–shell microneedle platform that aligns drug delivery with SCI progression by temporally decoupling the release kinetics of distinct therapeutics. The shell enabled rapid methylprednisolone (MP) release to suppress inflammatory cascades and restrict the expansion of secondary injury during the acute phase, while the core achieved sustained release of miR124-enriched M2 macrophage-derived exosomes (M2-miR124-Exo), promoting neuroprotection and microenvironmental remodeling during the subacute phase. This “suppression-then-repair” strategy synchronized treatment timing with stage-specific pathological demands, overcoming the limitations of conventional single-window delivery systems. Mechanistically, the platform promoted neuronal survival and axonal regeneration partly through modulation of key signaling pathways, including MAPK. In vivo, the platform markedly improved locomotor recovery in SCI rats, reduced lesion size, and exhibited no detectable systemic toxicity. These findings establish a programmable, pathology-guided delivery paradigm that addresses the spatiotemporal mismatch in SCI therapy and offers a promising strategy for precision intervention in complex CNS injuries.