Nose-to-brain delivery of biomineralized silk fibroin nanoparticles synergistically extinguish neuroinflammation for efficient depressive-like symptoms alleviation.

Abstract

Major depressive disorder (MDD) represents a prevalent psychiatric health problem with typically neuroinflammation and microglial overactivation. Efficiently delivering therapeutic medications across the blood-brain barrier for neuroinflammation depletion remains currently unavailable. Hence, we developed the biomineralized silk fibroin nanoparticles (CaSF@TB) for intranasal delivery of tetrahydroxystilbene glucoside and berberine to target the brain in addressing depressive disorders. CaSF@TB effectively increased AQP4 expression, promoted microglial M2 polarization, and reduced inflammatory cytokines in LPS-stimulated BV2 cells. Meanwhile, intranasal delivery of CaSF@TB enabled reliable brain targeting with minimal systemic distribution. In the MDD mice model, CaSF@TB significantly improved behavioral outcomes (p&#xa0;<&#xa0;0.0001) and enhanced BDNF expression with &#x223c;6.2 fold higher than that of the MDD group, which was achieved through the synergistic effect of M2-like polarization, microglial restoration, and neuroinflammatory elimination in the hippocampus region. No toxicity was observed in major organs or blood indicators. These findings indicated that CaSF@TB offered a safe and efficient strategy for MDD treatment through the nasal route, which holds great potential for future bioapplications.