Exosome-based targeted delivery of NF-κB ameliorates age-related neuroinflammation in the aged mouse brain

Abstract

Neuroinflammation, a significant contributor to various neurodegenerative diseases, is strongly associated with the aging process; however, to date, no efficacious treatments for neuroinflammation have been developed. In aged mouse brains, the number of infiltrating immune cells increases, and the key transcription factor associated with increased chemokine levels is nuclear factor kappa B (NF-κB). Exosomes are potent therapeutics or drug delivery vehicles for various materials, including proteins and regulatory genes, to target cells. In the present study, we evaluated the therapeutic efficacy of exosomes loaded with a nondegradable form of IκB (Exo-srIκB), which inhibits the nuclear translocation of NF-κB to suppress age-related neuroinflammation. Single-cell RNA sequencing revealed that these anti-inflammatory exosomes targeted macrophages and microglia, reducing the expression of inflammation-related genes. Treatment with Exo-srIκB also suppressed the interactions between macrophages/microglia and T and B cells in the aged brain. We demonstrated that Exo-srIκB successfully alleviates neuroinflammation by primarily targeting activated macrophages and partially modulating the functions of age-related interferon-responsive microglia in the brain. Thus, our findings highlight Exo-srIκB as a potential therapeutic agent for treating age-related neuroinflammation. As we age, our bodies undergo changes that can lead to diseases like Alzheimer’s and Parkinson’s. A key factor in this process is inflammation in the brain, driven by a protein called NF-κB. Researcher explored a new way to reduce this inflammation using tiny particles called exosomes. These exosomes were engineered to carry a special form of a protein that blocks NF-κB, called srIκB. In their study, the team injected these exosomes into mice and observed their effects on neuroinflammation. They used advanced techniques to analyze changes in cells of the brain and found that the exosomes reduced inflammation-related genes and altered immune cell behavior. This suggests that the exosomes can help control inflammation in the aging brain. The results indicate that these engineered exosomes could be a promising treatment for age-related brain diseases. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.