Smart nanocarriers and biomaterials for targeted drug delivery in spinal cord injury: molecular mechanisms and translational perspectives

Abstract

Spinal cord injury (SCI) results in permanent motor, sensory, and autonomic dysfunction below the level of injury; currently, there are no effective treatments to promote neural functional recovery. Inflammatory responses, oxidative stress, apoptosis, excitotoxicity, glial scarring, and impaired axonal regeneration—all triggered by secondary damage—are the core pathological mechanisms hindering functional recovery. Traditional drugs, however, are limited by the blood-spinal cord barrier, short half-lives, and systemic toxic side effects, resulting in poor therapeutic efficacy. This article provides a systematic review of research progress over the past decade on the use of nanocarrier-based therapeutics for the treatment of spinal cord injury and analyzes their therapeutic effects through seven major mechanisms, including the inhibition of inflammation and regulation of macrophage/microglia polarization, antagonism of oxidative stress, regulation of programmed cell death and neuroprotection, as well as the promotion of axonal regeneration, myelin repair, glial scar and extracellular matrix remodeling, and vascular repair and blood-spinal cord barrier reconstruction. It further compares the functional characteristics, advantages, and translational potential of major delivery platforms, including liposomes, polymeric nanoparticles, micelles, inorganic nanomaterials, nanozymes, exosomes, biomimetic carriers, nanohydrogels, and composite scaffolds. Among these, biomimetic carriers and multifunctional nanozymes have shown promising preclinical results in trans-barrier delivery and modulation of the injury microenvironment. However, current research still faces bottlenecks such as insufficient long-term safety validation, low targeting efficiency, significant discrepancies between animal models and clinical pathology, and difficulties in scaling up preparation processes. By integrating the characteristics of nanocarriers with the key pathological mechanisms at different stages of spinal cord injury, this paper provides a mechanism-driven analytical framework for the rational design and clinical translation of nanomedicines. In the future, microenvironment-responsive smart delivery, the integration of nanotechnology with stem cells and neuromodulation strategies, and the establishment of standardized evaluation systems may become key directions for advancing the clinical translation of nanomedicines.