Targeting Inflammatory Microglia in the Treatment of Neurodegenerative Disease

The immune cells of the central nervous system are distinct from those of the rest of the body. Innate immune cells such as microglia become increasingly inflammatory with advancing age, and this is very disruptive of tissue function in the brain. This progression into a state of chronic inflammation is an important component of many neurodegenerative conditions. Some of this is due to growing levels of cellular senescence in these cell populations, and with the advent of senolytic therapies to selectively destroy senescent cells, some reversal of neurodegeneration has been demonstrated in animal models. Not all inflammatory microglia are senescent, however, and it seems likely that the causes of the more general overactivation of such cells will also need to be addressed.

Advances in nanotechnology have enabled the design of nanotherapeutic platforms that could address the challenges of targeted delivery of active therapeutic agents to the central nervous system (CNS). While the majority of previous research studies on CNS nanotherapeutics have focused on neurons and endothelial cells, the predominant resident immune cells of the CNS, microglia, are also emerging as a promising cellular target for neurodegeneration considering their prominent role in neuroinflammation. Under normal physiological conditions, microglia protect neurons by removing pathological agents. However, long-term exposure of microglia to stimulants will cause sustained activation and lead to neuronal damage due to the release of pro-inflammatory agents, resulting in neuroinflammation and neurodegeneration.

This perspective highlights criteria to be considered when designing microglia-targeting nanotherapeutics for the treatment of neurodegenerative disorders. These criteria include conjugating specific microglial receptor-targeting ligands or peptides to the nanoparticle surface to achieve targeted delivery, leveraging microglial phagocytic properties, and utilizing biocompatible and biodegradable nanomaterials with low immune reactivity and neurotoxicity. In addition, certain therapeutic agents for the controlled inhibition of toxic protein aggregation and for modulation of microglial activation pathways can also be incorporated within the nanoparticle structure without compromising stability. Overall, considering the multifaceted disease mechanisms of neurodegeneration, microglia-targeted nanodrugs and nanotherapeutic particles may have the potential to resolve multiple pathological determinants of the disease and to guide a shift in the microglial phenotype spectrum toward a more neuroprotective state.



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