ROS-responsive Vitamin D ₃ -loaded hyaluronic acid injectable hydrogel enhances PPARγ-mediated neuroprotection in an in vitro model of depression

Oxidative stress is a major contributor to neuronal injury in depression and requires neuroprotective approaches. In this work, we designed a reactive oxygen species (ROS)-sensitive HA injectable hydrogel for controlled Vitamin D3 delivery. The hydrogel is synthesized by carbodimide conjugation of a thioketal ROS-sensitive linker and then loaded with Vitamin D3. Physicochemical characterization demonstrated appropriate hydrogel network formation, surface charge, efficient drug loading (DL) and amorphous drug dispersion within the hydrogel matrix. This formulation displayed quick gelation, stable viscoelastic properties and ROS-triggered degradation with increased drug release in oxidative environments. Vitamin D3-loaded hydrogel remarkably enhanced cell viability, inhibited intracellular ROS, maintained mitochondrial membrane potential (MMP) and averted caspase-dependent apoptosis in corticosterone (CORT) treated SH-SY5Y neuronal cells. It also restored antioxidant defenses and activated PPARγ/Nrf2/BDNF signaling, altering apoptosis-associated genes. This ROS-sensitive HA hydrogel that not only potentiated neuroprotective effects of Vitamin D3 but also provides a potential strategy for treating oxidative stress–associated depression.