Liposome-Based Therapeutics: A Novel Strategy to Mitigate Microglial Activation and Neuroinflammation in Neurodegenerative Diseases

Background: Microglia, the resident immune cells of the central nervous system (CNS), play a key role in immune defense and inflammatory responses in the brain. As primary modulators of neuroinflammation, microglia release proinflammatory cytokines, nitric oxide (NO), and reactive oxygen species (ROS) in response to various stimuli. While essential for immune response, these inflammatory processes contribute to the progression of neurodegenerative diseases such as Alzheimer’s disease (AD) and Parkinson’s disease (PD). Effective treatments for these conditions are limited, partly due to the challenge of crossing the blood-brain barrier (BBB). Encapsulation of therapeutic agents in liposomal vesicles has shown potential to improve drug delivery across the BBB and enable targeted delivery to brain cells. Objective: Evaluate the safety, cellular uptake, and anti-inflammatory effects of liposome formulations on activated microglial cells, with the aim of developing liposome-based therapeutic strategies capable of crossing the blood-brain barrier to mitigate neuroinflammation. Methods: In this study, we synthesized six liposome formulations incorporating DOPC, cholesterol, PEG-2000, t-butanol and an anti-inflammatory compound to evaluate their effects on microglial cell health, ROS production, and IL-6 cytokine release in IFN-gamma-activated human microglial (HMC3) cells. Cytotoxicity was assessed using MTT assays, ROS production by flow cytometry, gene expression by real-time PCR, and cytokine release by ELISA. Results: Our results indicate that all liposome formulations were safe for microglial cells at concentrations below 100 μg/mL, with no significant cytotoxicity. Notably, Liposome 2 effectively reduced ROS levels and proinflammatory cytokine release in activated microglia (p < 0.05, n = 4), suggesting an anti-inflammatory effect. Additionally, Liposomes 2, 4, and 6 demonstrated efficient internalization within microglial cells, indicating their suitability for CNS drug delivery. Conclusion: These findings suggest that Liposome 2 may inhibit microglial activation without toxicity, supporting the potential of liposome-based therapies for managing neuroinflammation in neurodegenerative diseases. This work provides a foundation for developing novel treatments aimed at AD and PD. This project was funded by 2023 EnTRUST Program from Puerto Rico Science, Technology & Research Trust to YIN. This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.