Hierarchical microtopology and phase-specific delivery functionally restore ultralong nerve continuity across species

Repairing ultralong peripheral nerve defects remains a major clinical challenge, primarily due to the requirement for regenerative platforms to be capable of integrating spatial guidance with temporally resolved biochemical cues. To address this, we developed a clinically translatable, fully synthetic nerve conduit that aligns with native regenerative principles through hierarchical microtopological engineering and phase-specific molecular delivery. This design creates a proregenerative microenvironment by synchronizing structural cues with repair cascades. The neuroanatomically inspired core mimics the endoneurium and perineurium, providing extensive cell-scale contact guidance for axonal alignment and fasciculation. A dual-layered sheath ensures mechanical integrity, metabolic permeability, and selective exclusion of fibrotic tissue. Tailored to align with distinct phases of nerve repair, the conduit enables sequential release of spermidine and ascorbic acid. Spermidine resolves early inflammation, priming the niche for ascorbic acid-mediated debris clearance, axonal elongation, and remyelination. In both rat (2 centimeters) and beagle (5 centimeters) models of critical-sized sciatic nerve defects, the conduit supports structural and functional regeneration comparable to autografts while yielding superior outcomes in motor coordination and suppression of autotomy. This strategy offers a scalable and mechanistically informed solution for repairing ultralong nerve injuries with high translational promise.