As a group of progressive, chronic, and disabling disorders, neurodegenerative diseases (NDs) affect millions of people worldwide, and are on the rise. NDs are known as the gradual loss of neurons; however, their pathophysiological mechanisms have not been precisely revealed. Due to the complex pathophysiological mechanisms behind the neurodegeneration, investigating effective and multi-target treatments has remained a clinical challenge. Besides, appropriate neuroprotective agents are still lacking, which raises the need for new therapeutic agents. In recent years, several reports have introduced naturally-derived compounds as promising alternative treatments for NDs. Among natural entities, flavonoids are multi-target alternatives affecting different pathogenesis mechanisms in neurodegeneration. Naringenin is a natural flavonoid possessing neuroprotective activities. Increasing evidence has attained special attention on the variety of therapeutic targets along with complex signaling pathways for naringenin, which suggest its possible therapeutic applications in several NDs. Here, in this review, the neuroprotective effects of naringenin, as well as its related pharmacological targets, signaling pathways, molecular mechanisms, and clinical perspective, are described. Moreover, the need to develop novel naringenin delivery systems is also discussed to solve its widespread pharmacokinetic limitation.

Recent advancements in gene expression modulation and RNA delivery systems have underscored the immense potential of nucleic acid-based therapies (NA-BTs) in biological research. However, the blood–brain barrier (BBB), a crucial regulatory structure that safeguards brain function, presents a significant obstacle to the delivery of drugs to glial cells and neurons. The BBB tightly regulates the movement of substances from the bloodstream into the brain, permitting only small molecules to pass through. This selective permeability poses a significant challenge for effective therapeutic delivery, especially in the case of NA-BTs. Extracellular vesicles, particularly exosomes, are recognized as valuable reservoirs of potential biomarkers and therapeutic targets. They are also gaining significant attention as innovative drug and nucleic acid delivery (NAD) carriers. Their unique ability to safeguard and transport genetic material, inherent biocompatibility, and capacity to traverse physiological barriers highlight their potential as drug carriers. This review provides a comprehensive overview of current strategies to enhance NAD to the brain, focusing on the emerging potential of exosomes as biocompatible and efficient nanocarriers. It synthesizes recent advances in the use of exosomes for NA-BTs in neurological disorders, comparing their advantages with those of conventional nanodelivery systems and cell-based therapies. Additionally, the review highlights innovative exosome engineering approaches to improve brain-targeted delivery, addresses key methodological limitations such as variability in cargo content, and proposes solutions to enhance standardization and safety. Collectively, these insights highlight the translational potential of exosomes and offer a novel perspective on bridging the gap between fundamental research and clinical application. Graphical Abstract