Targeting microglial circMBNL1 unlocks a novel nanomedicine therapeutic strategy for major depressive disorder

Major depressive disorder (MDD) is a prevalent psychological disorder that has a substantial effect on social and psychological functioning, requiring innovative treatments. Circular RNAs (circRNAs) have been shown to play a role in the pathogenesis of MDD and represent promising therapeutic targets. However, the target delivery strategies of interfering circRNAs against depression have not been extensively researched. Here, CircMBNL1 was identified to be significantly upregulated in plasma samples and showed a positive correlation with 24-Hamilton Depression Scale (HAMD-24) scores in patients with MDD. Moreover, in the microglia of the brains of mice subjected to the chronic unpredictable stress (CUS) model, circMBNL1 was significantly upregulated. To achieve specific knockdown of circMBNL1 in microglia, PEG/PEI-based nanoparticles were modified with MG1 peptide for the targeted delivery of siRNA (TNP-si-circMBNL1) into activated microglia via intranasal administration. In vitro and in vivo studies demonstrated that TNP-si-circMBNL1 efficiently delivered si-circMBNL1 to activated microglia, resulting in a significant reduction in circMBNL1 expression. Notably, intranasal administration of TNP-si-circMBNL1 effectively ameliorated CUS-induced depressive-like behaviors in mice. These results indicate that circMBNL1 is linked to MDD, and the peptide-guided nanoparticle loaded siRNA targeting circMBNL1 (TNP-si-circMBNL1) displays great potential for depression therapy.