An Olsalazine-LoadedHollow Mesoporous Prussian Blue/PolydopamineNanozyme Alleviates Anxiety/Depression-like Behavior and EnhancesBrain Neural Activity in Colitis Mice

Individuals diagnosed with inflammatory bowel disease (IBD) exhibit a markedly elevated prevalence of psychiatric disorders, particularly anxiety and depression. However, the underlying mechanisms contributing to the development of these psychiatric conditions in IBD patients remain poorly understood, and no effective therapeutic strategy has been definitively established. Recent advancements in nanotechnology-based interventions offer promising potential for restoring gut homeostasis, which may mitigate inflammation and oxidative stress associated with IBD. Herein, we first synthesized hollow mesoporous Prussian blue (HMPB)/polydopamine (HMPB/PDA) nanoparticles (NPs), followed by physical loading with olsalazine (Olsa) (Olsa@HMPB/PDA NPs) to reshape intestinal homeostasis and relieve accompanying anxiety/depression-like behavior in colitis mice. The Olsa@HMPB/PDA NPs displayed a macroporous structure with high biocompatibility and reactive oxygen species scavenging activity and released the drug gradually in the inflammatory environment. It could enhance intestinal retention after oral gavage administration following IBD in mice. Mechanistically, the composite demonstrated efficacy in significantly reducing pro-inflammatory cytokine levels, regulated the polarization of macrophages, and attenuated mitochondrial dysfunction via its dual anti-inflammatory and antioxidant properties, ultimately leading to substantial mitigation of colitis symptoms in IBD mice. Furthermore, we found that dextran sodium sulfate (DSS) induced microglia activation and decreased neuronal activation in the CA1 hippocampus of mice, associated with anxiety/depression-like behavior. As the observed modulation of the dysfunction of neuroinflammation and neuronal activation of CA1 hippocampus, Olsa@HMPB/PDA NPs treatment alleviated anxiety/depression-like behavior in DSS mice. Overall, this nanozyme established a paradigm in combined IBD therapy with psychological comorbidities.