Liposomal Co-Loaded Taxifolin–Melatonin Formulation to MitigateNeuroinflammation via PPAR-γ Modulation

Introduction: Neuroinflammation associated with microglial activation, oxidative stress, and cytokine release plays a central role in neuronal dysfunction in neurodegenerative disorders. Melatonin and taxifolin possess complementary antioxidant and anti-inflammatory actions but are limited by low solubility and stability. This study aimed to develop a dual-drug, taxifolin-decorated liposomal system to enhance synergistic modulation of inflammatory and oxidative pathways in activated microglia. Methods: Co-loaded melatonin–taxifolin liposomes were prepared by thin-film hydration followed by probe sonication and surface decoration via thiol–maleimide conjugation. Physicochemical evaluation included particle size, PDI, zeta potential, encapsulation efficiency, and in-vitro release. BV2 microglial assays evaluated cell viability (MTT), ROS generation, cytokine secretion, and expression of PPAR-γ, NF-κB p65, and cleaved caspase-3. Indirect neuroprotection was assessed in SH-SY5Y cells exposed to conditioned media from treated BV2 cultures. Results: The formulations yielded nanosized, monodisperse vesicles (~118–130 nm) with high encapsulation efficiency and sustained release. The decorated co-loaded formulation improved BV2 viability, significantly reduced ROS and pro-inflammatory cytokines, and favorably modulated PPAR-γ and NF-κB expression. Conditioned media from treated microglia enhanced SH-SY5Y neuronal survival compared with free drugs and single-agent liposomes. Discussion: Findings indicate synergistic antioxidant and anti-inflammatory effects associated with co-delivery and nanocarrier encapsulation. While results support microglial pathway modulation, interpretation remains preliminary due to in-vitro design and limited replicate size. Conclusion: The taxifolin-decorated, co-loaded liposomal system demonstrated promising in-vitro neuroprotective potential through regulation of oxidative stress and inflammatory signaling. Further studies incorporating BBB transport, pharmacokinetics, mechanistic validation, and in-vivo evaluation are required to confirm translational relevance.