Reconstructing regenerative niches in the central nervous system: Molecular and microenvironmental determinants of axonal regeneration.

Central nervous system (CNS) disorders, including spinal cord injury, stroke, multiple sclerosis, and motor neuron diseases, are major causes of long-term disability largely due to the persistent failure of axonal regeneration. Over recent decades, diverse strategies have been developed to overcome these barriers, including modulation of extracellular matrix composition, engineering of biomaterial scaffolds, and reactivation of intrinsic growth-associated signaling pathways. However, interventions targeting isolated molecular or environmental factors have produced limited regenerative outcomes. Here, we propose a conceptual framework in which neural repair is understood as the reconstruction of a permissive regenerative niche that aligns intrinsic neuronal growth programs with engineered extracellular microenvironments. We synthesize current knowledge on the cellular and molecular determinants of axonal regeneration and discuss how extracellular matrix architecture and biomaterial scaffolds provide instructive physical and biochemical cues that stabilize growth cones and guide axonal extension. In parallel, intrinsic strategies targeting pathways such as mTOR, STAT3, Krüppel-like factors, and the Lin28/let-7 axis can reestablish neuronal growth competence. Advanced in vitro platforms further enable controlled integration of intrinsic and extrinsic variables, providing experimental models of regenerative niches and testbeds for combinatorial interventions. By framing axonal regeneration as an emergent property of coordinated neuron-environment interactions, this review bridges neurobiology and bioengineering to propose a disease-relevant conceptual framework for neural repair and highlights the need for integrative strategies capable of aligning neuronal state with engineered extracellular landscapes.