Lysine-polydopamine nanoparticles for ameliorating acidic microenvironment and neuroprotection in spinal cord injury repair

Spinal cord injury (SCI) is exacerbated by the formation of an acidic microenvironment and extensive neuronal loss, both of which contribute to poor functional recovery. To address this, we developed lysine-polydopamine nanoparticles (Lys-PDA) as a multifunctional therapeutic platform for SCI. Lysine, a naturally occurring amino acid, possesses weak alkalinity and neuroprotective properties, but suffers from poor in vivo stability and non-specific distribution. Polydopamine (PDA), a biocompatible polymer with inherent antioxidant and anti-inflammatory capabilities, was employed as a nanocarrier to enhance lysine delivery and local retention. In vitro and in vivo assessments confirmed that Lys-PDA exhibit excellent biocompatibility and enable sustained release of lysine for up to three days. Upon administration into SCI mice, Lys-PDA significantly neutralized the acidic lesion milieu, with pH values increasing by approximately 0.33 units—approaching levels observed in uninjured spinal tissue. After 28 days of treatment, Lys-PDA markedly reduced neuronal apoptosis, suppressed reactive oxygen species (ROS) and lactate accumulation, and significantly improved hindlimb motor function. Behavioral analyses demonstrated a substantial increase in Basso Mouse Scale (BMS) scores from 0.0 to 5.8, alongside a corresponding increase in hindlimb stride length from 2.0 cm to 4.3 cm. Collectively, these findings suggest that Lys-PDA not only modulate the hostile post-injury microenvironment but also promote neuroprotection and functional recovery, positioning them as a promising candidate for SCI repair.