Nanodrug Delivery Systems for Myasthenia Gravis: Advances and Perspectives

Abstract

Myasthenia gravis (MG) is a rare chronic autoimmune disease caused by the production of autoantibodies against the postsynaptic membrane receptors present at the neuromuscular junction. This condition is characterized by fatigue and muscle weakness, including diplopia, ptosis, and systemic impairment. Emerging evidence suggests that in addition to immune dysregulation, the pathogenesis of MG may involve mitochondrial damage and ferroptosis. Mitochondria are the primary site of energy production, and the reactive oxygen species (ROS) generated due to mitochondrial dysfunction can induce ferroptosis. Nanomedicines have been extensively employed to treat various disorders due to their modifiability and good biocompatibility, but their application in MG management has been rather limited. Nevertheless, nanodrug delivery systems that carry immunomodulatory agents, anti-oxidants, or ferroptosis inhibitors could be effective for the treatment of MG. Therefore, this review focuses on various nanoplatforms aimed at attenuating immune dysregulation, restoring mitochondrial function, and inhibiting ferroptosis that could potentially serve as promising agents for targeted MG therapy.

Keywords: ferroptosis; immunomodulation; mitochondrial dysfunction; myasthenia gravis; nanomedicine.

Figure 1

Schematic showing the pathogenesis of acetylcholine receptor-related myasthenia gravis (AChR-MG). T cells interact with B cells, which further differentiate into plasma and memory B cells. The antibodies produced by plasma cells bind to the AChR in the postsynaptic membrane forming the membrane attack complex after binding to the complement, which results in the internalization and degradation of AChR and prevents normal neuromuscular transmission. Created using Figdraw2.0 (www.figdraw.com, accessed on 30 April 2024).

Figure 2

Mechanisms of mitochondrial damage and ferroptosis in MG. Oxidative stress in mitochondria leads to the production of ROS. This can increase membrane potential, mitochondrial swelling and lipid peroxidation, the dysregulation of mitochondrial dynamics, cytochrome C activity, and autophagy, resulting in apoptosis. Moreover, the ROS generated by excessive Fe²⁺ and the Fenton reaction also induce lipid peroxidation, promoting ferroptosis. Nuclear factor erythroid 2-related factor 2 (Nrf2) can upregulate glutathione peroxidase 4 (GPX4) to inhibit the production of ROS, thereby preventing lipid peroxidation and inhibiting cell death. Created using Figdraw 2.0 (www.figdraw.com, accessed on 30 April 2024).

Figure 3

Schematic diagram showing the distribution of iron in the human body. Around 60–75% of the body’s iron is present as part of hemoglobin and in the macrophages of the reticuloendothelial system. Skeletal muscle accounts for a significant 7–8% of the body’s iron, and 20–30% of the iron is stored in the liver. The daily absorption and loss of iron is about 1–2 mg. Created using Figdraw 2.0 (www.figdraw.com, accessed on 30 April 2024).