Exploring novel roles of lipid droplets and lipid metabolism in regulating inflammation and blood-brain barrier function in neurological diseases

Wei Wei^1,2,3*Luo Fu³Ting Luo³Zhongnan Hao¹Yongli Pan^1,4Wenqiang Xin⁵Lin Zhang^1,6Zhuhong Lai⁷Haitao Zhang³Hua Liu^3*

• ¹University Medical Center Göttingen, Göttingen, Germany
• ²University of Göttingen, Göttingen, Lower Saxony, Germany
• ³College of Medicine, Southwest Jiaotong University, Chengdu, Sichuan Province, China
• ⁴Shandong Provincial Hospital, Jinan, Shandong Province, China
• ⁵The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi Province, China
• ⁶School of Medicine, Shanghai Jiao Tong University, Shanghai, Shanghai Municipality, China
• ⁷Mianyang Central Hospital, Mianyang, Sichuan Province, China

The blood-brain barrier (BBB) is a critical structure that maintains the brain's homeostasis by regulating the transport of molecules and protecting it from harmful substances. However, in neurological diseases such as ischemic stroke, Alzheimer's disease, Parkinson's disease, and multiple sclerosis, the integrity and function of the BBB can be significantly compromised. In these conditions, BBB disruption leads to increased permeability, which facilitates neuroinflammation, exacerbates neuronal damage, and accelerates disease progression. Recent research has highlighted the potential of lipid-based carriers, including liposomes and lipid droplets (LDs), in modulating the BBB's integrity and function in various neurological diseases.Liposomes, with their ability to cross the BBB via mechanisms such as receptormediated transcytosis and carrier-mediated transport, are emerging as promising vehicles for the targeted delivery of therapeutic agents to the brain. These properties allow liposomes to effectively reduce infarct size and promote neuroprotection in ischemic stroke, as well as deliver drugs in the treatment of neurodegenerative diseases.Furthermore, LDs-dynamic regulators of lipid metabolism and cellular energy-play an essential role in maintaining cellular homeostasis, particularly during periods of stress when BBB function is compromised. These LDs help sustain cellular energy needs and modulate inflammatory responses, which are key factors in maintaining BBB integrity. Surface modifications of liposomes can further enhance their targeting efficiency, enabling them to selectively bind to specific brain cell types, including neurons, astrocytes, and microglia. This customization improves the precision of therapeutic delivery and supports the development of more tailored treatments.However, challenges such as immune responses, rapid clearance, and complement activation-related toxicity continue to hinder the broader application of liposomes and LDs in clinical settings.This review will focus on the roles of liposomes and LDs in regulating BBB integrity across a range of neurological diseases, discussing their potential for targeted drug delivery, neuroprotection, and the modulation of neuroinflammation. Additionally, we will explore the strategies being developed to address the limitations that currently restrict their clinical use.