Polysialic-Acid-Based Micelles Promote Neural Regeneration in Spinal Cord Injury Therapy

Spinal cord injury
(SCI) routinely causes the immediate loss and
disruption of neurons followed by complicated secondary injuries,
including inflammation, oxidative stress, and dense glial scar formation.
Inhibitory factors in the lesion scar and poor intrinsic neural regeneration
capacity restrict functional recovery after injury. Minocycline, which
has neuroprotective activity, can alleviate secondary injury, but
the long-term administration of this drug may cause toxicity. Polysialic
acid (PSA) is a large cell-surface carbohydrate that is critical for
central nervous system development and is capable of promoting precursor
cell migration, axon path finding, and synaptic remodeling; thus,
PSA plays a vital role in tissue repair and regeneration. Here, we
developed a PSA-based minocycline-loaded nanodrug delivery system
(PSM) for the synergistic therapy of spinal cord injury. The prepared
PSM exerted marked anti-inflammatory and neuroprotective activities
both in vitro and in vivo. The administration of PSM could significantly
protect neurons and myelin sheaths from damage, reduce the formation
of glial scar, recruit endogenous neural stem cells to the lesion
site, and promote the regeneration of neurons and the extension of
long axons throughout the glial scar, thereby largely improving the
locomotor function of SCI rats and exerting a superior therapeutic
effect. The findings might provide a novel strategy for SCI synergistic
therapy and the utilization of PSA in other central nervous system
diseases.

脊髓损伤（Spinal cord injury, SCI）通常会即刻造成神经元丢失与结构破坏，随后引发一系列复杂的继发性损伤，包括炎症、氧化应激以及致密胶质瘢痕形成。损伤瘢痕中的抑制因子与较弱的内在神经再生能力，共同限制了损伤后的功能恢复。米诺环素（Minocycline）具备神经保护活性，可减轻继发性损伤，但长期给药可能引发毒性反应。聚唾液酸（Polysialic acid, PSA）是一类关键的细胞表面碳水化合物，对中枢神经系统发育至关重要，能够促进前体细胞迁移、轴突寻路与突触重塑，因此在组织修复与再生中发挥重要作用。本研究构建了一种负载米诺环素的聚唾液酸纳米药物递送系统（PSM），用于脊髓损伤的协同治疗。所制备的PSM在体外（in vitro）与体内（in vivo）实验中均表现出显著的抗炎与神经保护活性。给予PSM可显著保护神经元与髓鞘免受损伤，减少胶质瘢痕形成，招募内源性神经干细胞至损伤部位，并促进神经元再生以及长轴突穿越胶质瘢痕延伸，从而大幅改善脊髓损伤大鼠的运动功能，展现出更优的治疗效果。本研究结果可为脊髓损伤的协同治疗以及聚唾液酸在其他中枢神经系统疾病中的应用提供全新策略。