The treatment of spinal cord injury (SCI) remains unsatisfactory owing to the complex pathophysiological microenvironments at the injury site and the limited regenerative potential of the central nervous system. Metformin has been proven in clinical and animal experiments to repair damaged structures and functions by promoting endogenous neurogenesis. However, in the early stage of acute SCI, the adverse pathophysiological microenvironment of the injury sites, such as reactive oxygen species and inflammatory factor storm, can prevent the activation of endogenous neural stem cells (NSCs) and the differentiation of NSCs into neurons, decreasing the whole repair effect. To address those issues, a series of robust and multifunctional natural polyphenol-metformin nanoparticles (polyphenol-Met NPs) were fabricated with pH-responsiveness and excellent antioxidative capacities. The resulting NPs possessed several favorable advantages: First, the NPs were composed of active ingredients with different biological properties, without the need for carriers; second, the pH-responsiveness feature could allow targeted drug delivery at the injured site; more importantly, NPs enabled drugs with different performances to exhibit strong synergistic effects. The results demonstrated that the improved microenvironment by natural polyphenols boosted the differentiation of activated NSCs into neurons and oligodendrocytes, which could efficiently repair the injured nerve structures and enhance the functional recovery of the SCI rats. This work highlighted the design and fabrication of robust and multifunctional NPs for SCI treatment via efficient microenvironmental regulation and targeted NSCs activation.

Robust and Multifunctional Nanoparticles Assembled from Natural Polyphenols and Metformin for Efficient Spinal Cord Regeneration.

Functional recovery following a spinal cord injury (SCI) is challenging. Traditional drug therapies focus on the suppression of immune responses; however, strategies for alleviating oxidative stress are lacking. Herein, we developed the zinc-organic framework (Zn@MOF)-based aggregation-induced emission-active nanozymes for accelerating recovery following SCI. A multifunctional Zn@MOF was modified with the aggregation-induced emission-active molecule 2-(4-azidobutyl)-6-(phenyl(4-(1,2,2-triphenylvinyl)phenyl)amino)-1H-phenalene-1,3-dione via a bioorthogonal reaction, and the resulting nanozymes were denoted as Zn@MOF-TPD. These nanozymes gradually released gallic acid and zinc ions (Zn2+) at the SCI site. The released gallic acid, a scavenger of reactive oxygen species (ROS), promoted antioxidation and alleviated inflammation, re-establishing the balance between ROS production and the antioxidant defense system. The released Zn2+ ions inhibited the activity of matrix metalloproteinase 9 (MMP-9) to facilitate the regeneration of neurons via the ROS-mediated NF-κB pathway following secondary SCI. In addition, Zn@MOF-TPD protected neurons and myelin sheaths against trauma, inhibited glial scar formation, and promoted the proliferation and differentiation of neural stem cells, thereby facilitating the repair of neurons and injured spinal cord tissue and promoting functional recovery in rats with contusive SCI. Altogether, this study suggests that Zn@MOF-TPD nanozymes possess a potential for alleviating oxidative stress-mediated pathophysiological damage and promoting motor recovery following SCI.

Engineered Multifunctional Zinc-Organic Framework-Based Aggregation-Induced Emission Nanozyme for Accelerating Spinal Cord Injury Recovery.

Abstract Epilepsy is a prevalent neurological disorder characterized by unprovoked seizures. γ-Aminobutyric acid (GABA) serves as the primary fast inhibitory neurotransmitter in the brain, and GABA binding to the GABA A receptor (GABA A R) regulates Cl - and bicarbonate (HCO 3 - ) influx or efflux through the channel pore, leading to GABAergic inhibition or excitation, respectively. The neuron-specific K + -Cl - cotransporter 2 (KCC2) is essential for maintaining a low intracellular Cl - concentration, ensuring GABA A R-mediated inhibition. Impaired KCC2 function results in GABAergic excitation associated with epileptic activity. Loss-of-function mutations and altered expression of KCC2 lead to elevated [Cl - ] i and compromised synaptic inhibition, contributing to epilepsy pathogenesis in human patients. KCC2 antagonism studies demonstrate the necessity of limiting neuronal hyperexcitability within the brain, as reduced KCC2 functioning leads to seizure activity. Strategies focusing on direct (enhancing KCC2 activation) and indirect KCC2 modulation (altering KCC2 phosphorylation and transcription) have proven effective in attenuating seizure severity and exhibiting anti-convulsant properties. These findings highlight KCC2 as a promising therapeutic target for treating epilepsy. Recent advances in understanding KCC2 regulatory mechanisms, particularly via signaling pathways such as WNK, PKC, BDNF, and its receptor TrkB, have led to the discovery of novel small molecules that modulate KCC2. Inhibiting WNK kinase or utilizing newly discovered KCC2 agonists has demonstrated KCC2 activation and seizure attenuation in animal models. This review discusses the role of KCC2 in epilepsy and evaluates its potential as a drug target for epilepsy treatment by exploring various strategies to regulate KCC2 activity. 

Neuronal K+-Cl- cotransporter KCC2 as a promising drug target for epilepsy treatment.

Bone-marrow-homing lipid nanoparticles for genome editing in diseased and malignant haematopoietic stem cells.

Rationale: Spinal cord injury (SCI) results in neural tissue damage. However, the limited regenerative capacity of adult mammals' axons upon SCI leads to persistent neurological dysfunction. Thus, exploring the pathways that can enhance axon regeneration in injured spinal cord is of great significance. Methods: Through the utilization of single-cell RNA sequencing in this research, a distinct subpopulation of bone marrow mesenchymal stem cells (BMSCs) that exhibits the capacity to facilitate axon regeneration has been discovered. Subsequently, the CD271 + CD56 + BMSCs subpopulation was isolated using flow cytometry, and the exosomes derived from this subpopulation (CD271 + CD56 + BMSC-Exos) were extracted and incorporated into a hydrogel to create a sustained release system. The aim was to investigate the therapeutic effects of CD271 + CD56 + BMSC-Exos and elucidate the underlying mechanisms involved in promoting axon regeneration and neural function recovery. Results: The findings indicate that CD271 + CD56 + BMSC-Exos share similar physical and chemical properties with conventional exosomes. Importantly, in an SCI model, in situ implantation of CD271 + CD56 + BMSC-Exos hydrogel resulted in increased expression of NF and synaptophysin, markers associated with axon regeneration and synapse formation, respectively. This intervention also contributed to improved neural function recovery. In vitro experiments demonstrated that CD271 + CD56 + BMSC-Exos treatment significantly enhanced axon extension distance and increased the number of branches in dorsal root ganglion axons. Moreover, further investigation into the molecular mechanisms underlying CD271 + CD56 + BMSC-Exos-mediated axon regeneration revealed the crucial involvement of the miR-431-3p/RGMA axis. Conclusion: In summary, the implantation of CD271 + CD56 + BMSC-Exos hydrogel presents a promising and effective therapeutic approach for SCI.

Exosomes derived from CD271+CD56+ bone marrow mesenchymal stem cell subpopoulation identified by single-cell RNA sequencing promote axon regeneration after spinal cord injury

Controlled delivery of a neurotransmitter-agonist conjugate for functional recovery after severe spinal cord injury.

Despite tremendous unmet medical needs, there is no effective pharmacological treatment to promote functional recovery after spinal cord injury (SCI). Although multiple pathological events have been implicated in SCI, the development of a noninvasive pharmacological approach to simultaneously target the different mechanisms involved in SCI remains a formidable challenge. In this study, we report the development of a noninvasive nanodrug delivery system that consists of ROS-responsive amphiphilic copolymers and an encapsulated neurotransmitter-conjugated KCC2 agonist. We show that upon intravenous administration, the nanodrugs were able to enter the injured spinal cord due to blood spinal cord barrier disruption and ROS-responsive disassembly. Remarkably, once in the injured spinal cord, these nanodrugs exhibited dual functions: scavenging ROS accumulated in the lesion to protect spared connections and increasing neuronal excitability in the injured spinal cord through targeted delivery of the KCC2 agonist to inhibitory neurons. Thus, the noninvasive treatment led to significant functional recovery in the rats with contusive SCI. Together, these findings provide a much-needed translational pharmacological approach for treating severe SCI.

Improving functional recovery after severe spinal cord injury by a noninvasive dual functional approach of neuroprotection and neuromodulation

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Controlled delivery of a neurotransmitter-agonist conjugate for functional recovery after severe spinal cord injury.

Improving functional recovery after severe spinal cord injury by a noninvasive dual functional approach of neuroprotection and neuromodulation