Engineering metal-ion microenvironment modulation for spinal cord injury: from controlled release platforms to regeneration

Spinal cord injury (SCI) remains a major cause of long-term disability, largely because the adult central nervous system has limited intrinsic regenerative capacity and is further constrained by secondary injury cascades, including neuroinflammation, blood–spinal cord barrier disruption, oxidative stress, glial scarring, and progressive cell death. In recent years, metal ions have emerged as promising modulators of the post-injury microenvironment due to their distinct coordination chemistry and biological functions, enabling multi-pathway regulation of immune responses, redox homeostasis, cell survival, axonal regeneration, and synaptic plasticity. However, free-ion administration is hindered by rapid diffusion, uncontrolled biodistribution, and potential systemic toxicity, highlighting the need to precisely control the “dose–time–target” relationship in vivo . This review summarizes current advances in metal-ion-based strategies for SCI repair, with an emphasis on biomaterial-enabled spatiotemporal delivery platforms, including hydrogels, scaffolds, nanoparticles, and metal–organic frameworks. We compare biodegradable versus non-biodegradable metal-related systems and discuss representative ion modalities (Zn 2+ , Mg 2+ , Li + , Ca 2+ , Fe 2+ /Fe 3+ , and gold-based nanomaterials), detailing their mechanisms in immune modulation, antioxidation/ferroptosis regulation, neuroprotection, and regeneration. We further highlight multi-ion combination approaches that align stage-specific ion signaling with the acute, subacute, and chronic phases of SCI pathology to enable synergistic, multi-target intervention. Finally, we analyze key translational challenges—including release precision, long-term biosafety, and individualized regimen design—and propose future directions for clinically oriented, programmable metal-ion therapies.