NEW NANOPARTICLE-BASED THERAPEUTIC STRATEGIES TARGETING STRESS-RESPONSIVE MIRNAS IN A DEPRESSION-LIKE MOUSE MODEL

Major depressive disorder (MDD) is the most prevalent mental illness worldwide and a leading cause of suicide, with a higher incidence in females. Its molecular basis involves genetic, epigenetic, and environmental factors converging in emotion-regulating brain circuits. MicroRNAs (miRNAs), short non-coding RNA transcripts, are key post-transcriptional regulators of gene expression and mediate cellular responses to stress, although the mechanisms are not fully understood. A corticosterone-induced depression-like mouse model was generated and treated with ketamine. Behavioral assessments were performed, followed by miRNA sequencing of the medial prefrontal cortex (mPFC) and hippocampus (HPC). Differentially expressed miRNAs were validated by qPCR. Three robustly regulated miRNAs were selected for target prediction and over-representation analyses. AgomiRs and antagomiRs targeting these miRNAs were generated and encapsulated into nanoparticles (NPs). NP biodistribution was evaluated, and neuronal cell cultures were treated with NPs to assess modulation of miRNA-regulated mRNAs. Ketamine reversed the corticosterone-induced depressive-like behavioral phenotype. Significant expression changes in miR-21a-3p, miR-92a-1-5p, and miR-223-3p were detected in corticosterone-treated animals and were modulated by ketamine. Target analyses revealed enrichment in neurotrophin signaling pathways and FoxO1, a stress-responsive hub. Encapsulated NPs efficiently delivered their cargo to brain cells and were subsequently cleared. In cell cultures, NP treatment modulated miRNA target mRNA levels, confirming functional regulation. In conclusion, stress- and ketamine-responsive miRNA alterations were identified in key brain regions of a depression-like mouse model. These findings highlight miRNAs as potential biomarkers and therapeutic targets for depression, suggesting that NP-based miRNA modulation could be explored as an approach to rescue stress-induced phenotypes.