Functionalized nanozyme delivery of a KCC2-activator conjugate for the promotion of functional recovery after acute spinal cord injury

Although spinal cord injury (SCI) can arise from various clinical causes, current therapeutic strategies remain largely ineffective in promoting functional recovery, primarily due to the complex and multifaceted pathophysiology of SCI. Developing pharmacological interventions that can address the diverse mechanisms involved remains a formidable challenge. Here, we confirmed the altered expression of the K⁺-Cl^- co-transporter 2 (KCC2) in a rat model of SCI through RNA sequencing. However, the therapeutic application of KCC2 agonists is limited by their poor penetration into the injured central nervous system (CNS), raising concerns about their clinical efficacy. To overcome these limitations, we developed a novel reactive oxygen species (ROS) responsive delivery platform for targeted administration of KCC2 agonists. Specifically, we encapsulated quercetin, a potent KCC2 activator, within a polymersome-based nanocarrier system, termed QZIF-polymersomes. This formulation enables ROS-triggered release of quercetin at the injury site, aiming to protect spared tissues and facilitate their integration into the host spinal cord by modulating neuronal repair pathways. Our results demonstrate that QZIF-polymersomes not only preserve residual spinal cord tissue but also enhance neuronal energy metabolism by promoting mitochondrial biogenesis and upregulating mitochondrial genes related to oxidative phosphorylation, including the respiratory chain subunit COXI (complex IV) and regulators such as UCP2 and TFAM. Moreover, this strategy significantly promoted remyelination within the lesion area. Together, these findings highlight QZIF-polymersomes as a promising ROS-responsive KCC2 agonist delivery system that enhances neuroprotection and metabolic support, ultimately facilitating functional recovery after SCI.