A novel anti-depression strategy utilizing γ-CD-MOFs delivery system for volatile oil from Alpiniae Oxyphyllae fructus - examining the mechanism of gut microbiota and neuroinflammation.

The volatile oil extracted from Alpiniae Oxyphyllae Fructus (AOVO) exhibits excellent anti-inflammatory properties but is unstable. Therefore, this study aimed to develop a cyclodextrin-based drug delivery system employing γ-cyclodextrin metal-organic frameworks (γ-CD-MOFs) to encapsulate AOVO, and examine its potential antidepressant mechanisms by integrating multi-omics approaches. The AOVO/γ-CD-MOFs system exhibited a well-ordered crystalline structure. Physicochemical analyses confirmed the successful encapsulation of AOVO within the γ-CD-MOFs matrix. This encapsulation enhanced the stability, solubility, and cumulative release rate of AOVO, augmenting its biosafety, and antidepressant effects of AOVO in vivo. Based on the predicted antidepressant mechanisms of the identified components of AOVO in vivo, the current study confirmed that the formulation improved the integrity of the intestinal barrier and reduced the level of pro-inflammatory cytokines, which were positively associated with the increased abundance of Ligilactobacillus. This shift helped in antagonizing the cascade of responses associated with neuroinflammation triggered by the peripheral inflammatory stimulation. Meanwhile, AOVO/γ-CD-MOFs prolonged fluorescence signals in brain and alleviated neuroinflammation, thereby exerting an antidepressant effect. Overall, this study developed a promising food-grade strategy for encapsulating and stabilizing volatile oil therapeutic agents, and proposed a new scheme for treating depression using the fabricated AOVO/γ-CD-MOFs system. These findings provide a preclinical proof-of-concept for using food-grade γ-CD-MOFs to stabilize volatile oil therapeutic agents and improve their delivery performance.