Hydrogels with Biomineralized MnO2 Nanoparticles Promote Spinal Cord Injury Repair by Changing the Redox Microenvironment and Reducing Ferroptosis

Yong Liue^*
*Correspondence: Yong Liue, Department of Orthopaedic Surgery, The First Affiliated Hospital of Soochow University, 899 Pinghai Rd, Suzhou 215031, China, Email:

Introduction

Spinal cord injury is a devastating neurological condition that results in significant motor and sensory deficits due to the irreversible damage to the central nervous system. The complexity of SCI repair lies in the intricate cascade of secondary injury mechanisms following the initial trauma, which includes oxidative stress, inflammation, apoptosis, and more recently identified cell death pathways like ferroptosis. Traditional therapeutic approaches for SCI have been largely limited to symptom management, with very few strategies available to promote effective neural repair and functional recovery. Recent advances in nanomedicine and biomaterials, however, have provided new hope for treating SCI. One such approach involves the use of hydrogels combined with biomineralized manganese dioxide nanoparticles. These nanoparticles are known for their potent antioxidant properties and their ability to alter the redox microenvironment, which can directly impact the progression of secondary injury. In particular, MnO2 nanoparticles embedded in hydrogels have shown potential to reduce oxidative stress and mitigate ferroptosis, a form of iron-dependent cell death that has gained attention as a critical contributor to neural degeneration following SCI. By addressing these key pathological features, hydrogels containing MnO₂ nanoparticles offer a promising therapeutic strategy for SCI repair. This article will explore the mechanisms by which hydrogels with biomineralized MnO₂ nanoparticles promote SCI repair, focusing on their ability to change the redox microenvironment and reduce ferroptosis. We will also discuss the implications of these findings for the future of SCI treatment [1-3].

Description

Ferroptosis is a form of regulated cell death that is distinct from apoptosis and necrosis. It is characterized by the accumulation of lipid peroxides, which leads to the destruction of cell membranes. The process is iron-dependent, with iron-catalyzed reactions driving the production of harmful ROS. Unlike apoptosis, which is a relatively controlled process, ferroptosis is highly destructive, causing widespread damage to neural tissues. In the context of SCI, ferroptosis has been shown to contribute significantly to the degeneration of neurons and oligodendrocytes. The spinal cord is particularly vulnerable to ferroptosis due to its high iron content and low levels of endogenous antioxidant defenses. Targeting ferroptosis, therefore, represents a promising strategy to limit secondary damage and promote neural repair after SCI. Manganese dioxide nanoparticles have been extensively studied for their unique chemical properties, particularly their ability to catalyze the breakdown of ROS.

MnO₂ nanoparticles act as superoxide dismutase mimetics, converting harmful superoxide anions into less reactive species such as molecular oxygen and hydrogen peroxide. Additionally, they can degrade hydrogen peroxide into water, further reducing oxidative stress in damaged tissues. The process of biomineralization involves the incorporation of MnO₂ nanoparticles into biocompatible hydrogels. This ensures that the nanoparticles remain localized at the injury site and are slowly released over time, providing sustained antioxidant activity. The hydrogels also create a supportive scaffold for neural tissue regeneration by providing a three-dimensional matrix that mimics the extracellular environment. The redox microenvironment refers to the balance between pro-oxidant and antioxidant forces within a tissue. After SCI, the redox balance is heavily skewed towards pro-oxidants, leading to oxidative stress. MnO₂ nanoparticles embedded in hydrogels are designed to counteract this imbalance by scavenging ROS and restoring redox homeostasis [4,5].

Conclusion

While hydrogels containing MnO₂ nanoparticles show great promise for SCI repair, several challenges remain. One of the primary concerns is the long-term biocompatibility and potential toxicity of MnO₂ nanoparticles. Although preclinical studies have not shown significant toxicity, more research is needed to assess the long-term effects of MnO₂ nanoparticles in the CNS, particularly in human patients. One of the most exciting potential benefits of MnO₂ nanoparticles is their ability to reduce ferroptosis. As mentioned earlier, ferroptosis is driven by the accumulation of lipid peroxides, which are produced in large part due to oxidative stress. By scavenging ROS, MnO₂ nanoparticles directly reduce the formation of lipid peroxides, thereby inhibiting the key processes that lead to ferroptosis. MnO₂ nanoparticles limit the iron-catalyzed reactions that produce lipid peroxides. This prevents the destruction of cell membranes and preserves the integrity of neurons and oligodendrocytes at the injury site. Although MnO₂ nanoparticles do not directly chelate iron, their ability to reduce oxidative stress indirectly decreases the availability of free iron, which is necessary for the initiation of ferroptosis.

By modulating the iron-dependent production of ROS, MnO₂ nanoparticles help protect cells from ferroptotic death. The hydrogel matrix mimics the extracellular environment, providing a supportive scaffold for axonal sprouting and regrowth. This is crucial for re-establishing functional neural connections across the injury site. MnO₂ nanoparticles have been shown to promote the formation of new blood vessels (angiogenesis) by improving the local oxygen supply. This enhances tissue oxygenation and nutrient delivery, which are essential for neural regeneration. MnO₂ nanoparticles can activate signaling pathways that promote cell survival and reduce apoptosis. For example, they may upregulate neurotrophic factors like brain-derived neurotrophic factor, which supports the survival and growth of neurons.

Acknowledgement

None.

Conflict of Interest

None.

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