In vitro models of oxidative stress, mitochondrial dysfunction, and inflammation for evaluation of neuroprotective biomaterials

models that reproduce these distinct yet interconnected pathological features is essential for evaluating neuroprotective biomaterials. In this work, differentiated SH-SY5Y neuronal-like cells were used to establish complementary stress-induced models reflecting oxidative, mitochondrial, and inflammatory injury. Lipopolysaccharide (LPS), rotenone (Rot), and oligomycin A (Oli) were systematically assessed to define conditions that elicit reproducible neuronal damage, using our potassium persulfate (KPS) oxidative stress model as a reference for redox-mitochondrial interactions. Quantitative enzymatic assays and ELISA-based analyses showed that LPS activated NF-κB and IL-1β signaling with mild oxidative stress. Rot modulated Nrf2 and SOD expression, and Oli depleted ATP synthase while suppressing GSH-Px. To evaluate the translational relevance of these models, monoolein-plasmalogen (MPL) lipid liquid crystalline nanoparticles (LCNPs) were studied as neuroprotective assemblies loaded with melatonin or quercetin. MPL LCNPs demonstrated intrinsic antioxidant and mitochondrial-stabilizing activity, restoring ATP synthase activity, reducing intracellular ROS, and attenuating LPS-induced NF-κB activation. The presented multi-model framework provides a robust platform for characterizing neuronal stress responses and supports the rational design of neuroprotective biomaterials for neuroengineering and regenerative medicine.