MG1 peptide-guided nanoparticles delivering si-circMBNL1 ameliorate CUS-induced depressive behaviors in mice.

Major depressive disorder (MDD) is a highly prevalent and debilitating psychological condition significantly impacting social and psychological functioning, often requiring more effective and innovative treatments. Current standard-of-care antidepressants frequently have limited efficacy or undesirable side effects, highlighting a critical need for novel therapeutic strategies. Recent research has identified circular RNAs (circRNAs) as key regulators in MDD pathogenesis, making them promising targets for intervention. Specifically, circMBNL1 has been implicated, yet targeted delivery strategies for interfering with these circRNAs in depression remain largely unexplored. This study addresses the challenge of precise delivery to unlock circMBNL1 as a therapeutic target.

Researchers first identified circMBNL1 as significantly upregulated in plasma samples of MDD patients, showing a positive correlation with HAMD-24 scores. Concurrently, circMBNL1 was found to be significantly elevated in the microglia of mouse brains subjected to the chronic unpredictable stress (CUS) model. To specifically knock down circMBNL1 in microglia, a novel nanomedicine, TNP-si-circMBNL1, was engineered. This consisted of PEG/PEI-based nanoparticles modified with the MG1 peptide for targeted delivery of siRNA via intranasal administration. The team then conducted both in vitro and in vivo studies to evaluate the efficiency of si-circMBNL1 delivery to activated microglia and its subsequent impact on circMBNL1 expression and CUS-induced depressive-like behaviors in mice.

The investigation confirmed that circMBNL1 was significantly upregulated in MDD patient plasma, correlating positively with HAMD-24 scores, and similarly elevated in microglia from CUS mouse brains. In both in vitro and in vivo models, TNP-si-circMBNL1 demonstrated efficient and targeted delivery of si-circMBNL1 to activated microglia. This precise delivery resulted in a significant reduction in circMBNL1 expression within these cells. > Notably, intranasal administration of TNP-si-circMBNL1 effectively ameliorated CUS-induced depressive-like behaviors in mice, showcasing a direct therapeutic effect. These findings strongly link circMBNL1 to MDD and validate the MG1 peptide-guided nanoparticle system as a potent tool for targeted gene silencing in the brain.