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Major depressive disorder (MDD) is the most prevalent psychiatric disorder worldwide and severely limits psychosocial function and quality of life, but no effective medication is currently available. Circular RNAs (circRNAs) have been revealed to participate in the MDD pathological process. Targeted delivery of circRNAs without blood‐brain barrier (BBB) restriction for remission of MDD represents a promising approach for antidepressant therapy. In this study, RVG‐circDYM‐extracellular vesicles (RVG‐circDYM‐EVs) were engineered to target and preferentially transfer circDYM to the brain, and the effect on the pathological process in a chronic unpredictable stress (CUS) mouse model of depression was investigated. The results showed that RVG‐circDYM‐EVs were successfully purified by ultracentrifugation from overexpressed circDYM HEK 293T cells, and the characterization of RVG‐circDYM‐EVs was successfully demonstrated in terms of size, morphology and specific markers. Beyond demonstrating proof‐of‐concept for an RNA drug delivery technology, we observed that systemic administration of RVG‐circDYM‐EVs efficiently delivered circDYM to the brain, and alleviated CUS‐induced depressive‐like behaviours, and we discovered that RVG‐circDYM‐EVs notably inhibited microglial activation, BBB leakiness and peripheral immune cells infiltration, and attenuated astrocyte disfunction induced by CUS. CircDYM can bind mechanistically to the transcription factor TAF1 (TATA‐box binding protein associated factor 1), resulting in the decreased expression of its downstream target genes with consequently suppressed neuroinflammation. Taken together, our findings suggest that extracellular vesicle‐mediated delivery of circDYM is effective for MDD treatment and promising for clinical applications.

Psychosocial stress impacts immune system and brain function, yet mechanisms linking peripheral immune dysregulation to major depressive disorder remain unclear. Here, we demonstrate that a specific subset of T cells, the stem cell-like memory CD8 + T (T SCM ) cells, is elevated in patients and stress-susceptible mice. CD8 + T SCM cells from patients display unique transcriptional programs and correlated with depression severity. Adoptive transfer of stress-derived CD8⁺ T SCM cells induced depressive-like behavior and neuroinflammation in recipients, without brain migration. Employing a whole-body immunolabeling technology, we discover CD8 + T SCM cells migrated to intestine via the interaction of pro-platelet basic protein and C-X-C motif chemokine receptor 2. CD8 + T SCM cells decrease the abundance of tyrosine-metabolizing bacteria to reducing homovanillic acid production, triggered neuroinflammation and depressive symptoms. Thus, our findings uncover a complex interplay between CD8 + T SCM cells and gut microbial metabolism, shedding light on potential mechanisms underlying depression and suggesting avenues for therapeutic intervention. Major depressive disorder has been linked to peripheral immune dysfunction. Here, the authors identify elevated stem cell-like memory CD8⁺ T cells in patients and in a murine stress model show migration to the intestine via PPBP-CXCR2 and suggest gut CD8 cells modulate tyrosine metabolizing bacteria and homovanillic acid potentiating neuroinflammation and depressive phenotype.

RNA therapeutics have recently shown significant promise in treating a variety of diseases, including cancers, infectious diseases, and genetic disorders. However, their potential in addressing neuropsychiatric disorders has been limited by the lack of an efficient delivery system to the central nervous system (CNS). Here, a novel nanoemulsion platform, perillyl alcohol nanoemulsions (PANEs) is introduced, designed for the therapeutic delivery of circDYM to brain and alleviated depressive‐like behaviors. PANEs successfully encapsulated circDYM using cationic lipid compositions, enhancing its delivery efficiency to the mouse brain via its perillyl alcohol phase. The optimized formulation, PANE2‐4, significantly improved the brain delivery efficiency of circDYM compared to both free circDYM and standard lipid nanoparticle formulations. Intranasal administration of PANE2‐4‐circDYM effectively alleviated depressive‐like behaviors in the LPS‐induced mouse model of depression. This effect is achieved by reducing the CD11b+CD45dim microglia population and iNOS expression, restoring the expression of protein‐95 (PSD‐95) and synaptophysin. These findings indicated that PANE represents an efficient platform for delivering circRNAs to the brain, and intranasal administration of PANE2‐4‐circDYM is a promising strategy for ameliorating LPS‐induced depressive‐like behaviors. PANEs are specifically designed to enhance the brain delivery efficiency of circDYM compared to commercialized lipid nanoparticles (LNPs). Intranasal administration of PANE‐circDYM effectively alleviated LPS‐induced depressive‐like behaviors by mitigating neuroinflammation and promoting neuroplasticity. The histological assessment showed PANEs as a safe and effective RNA delivery system, highlighting the therapeutic potential of PANE2‐4‐circDYM for major depressive disorder.

Rationale. Selenium (Se) is a critical element for both maintaining human health and the growth of plants and animals. The content of Se in crops is primarily determined by its speciation in soil. Therefore, the investigation of soil Se and its speciation has become a key focus of current research.Methodology. In this study, taking a typical seleniferous area in Guiyang City as the study area, we investigated selenium speciation in Se-rich soil and its distribution characteristics in both soil and crops using atomic fluorescence spectroscopy (AFS) and a five-step extraction processing methods. Moreover, we further explored the key factors that affect the distribution of Se in soil.Results. The findings are summarised as follows: (1) the Se content in all investigated samples met the standards of selenium-rich soil (0.40 mg/kg). The Se content in the soil surrounding crop roots ranged from 0.96 to 4.29 mg/kg, with an average value of 2.18 mg/kg. (2) Soil Se primarily existed in organic, residual, and iron and manganese oxide-binding species. The organic, sulfide-binding, and elemental Se species were the major contributors, accounting for an average of 47.00%, while the content of water-soluble, exchangeable, and carbonate-binding Se species was significantly lower. (3) Almost all crops, regardless of their types, were found Se-enriched, accounting for approximately 89.47% of the total crops in the study area. The average Se content was 0.35, 0.12, and 0.026 mg/kg in tea, rice, and corn, respectively.Discussion. Varying soil physical–chemical properties, such as the content of soil organic matter content and pH levels, etc. can impact the distribution of Se in soil differently. These findings can serve as a scientific foundation for the effective utilisation of selenium-rich land resources in Guiyang city. They can also support and facilitate the development of modern specialty and high-efficiency mountain agriculture, ultimately contributing to rural revitalisation and the national implementation of the Big Ecology Strategy.