Geniposide-Loaded Biomimetic Nanoparticles Modulate HMOX1 To Alleviate Neuroinflammation in Depression

Depression is a debilitating mental disorder closely linked to neuroinflammation and dysregulated microglial activity. This study investigates a novel nanotherapeutic strategy utilizing geniposide (GEN)-loaded biomimetic nanoparticles (CSPG@CM) to target microglia and modulate heme oxygenase-1 (HMOX1), a key regulator of oxidative stress and neuroinflammation. Through the synergistic application of systems pharmacology frameworks, computational biological analysis, and both cell-based and animal experimental models, this study demonstrated that GEN-loaded nanoparticles significantly enhance drug bioavailability and specificity, facilitating precise microglial targeting. Treatment with CSPG@CM nanoparticles upregulates HMOX1 expression, suppresses pro-inflammatory cytokine release, and promotes neuronal survival. In a chronic unpredictable mild stress (CUMS) mouse model, CSPG@CM nanoparticles alleviate depressive behaviors, reduce neuroinflammation, and restore neuronal homeostasis. Compared to free GEN, the nanoparticle formulation exhibits superior therapeutic efficacy by overcoming limitations in traditional antidepressant treatments. These findings highlight the potential of nanoparticle-based drug delivery systems for precise modulation of neuroinflammatory pathways, offering a promising avenue for developing innovative antidepressant therapies.