Designing poly(gamma-aminobutyric acid)-based nanoparticles for the treatment of major depressive disorders

Major depressive disorder (MDD) is a worldwide concern owing to its negative impact on the quality of life. Gamma-aminobutyric acid (GABA), an essential neurotransmitter in the brain, is important for regulating the enteric nervous system and gut-brain dual communication (gut-brain axis), thus providing gastrointestinal GABA and GABA-related pathways with possible targets for MDD treatment. However, the use of GABA for this disease remains limited due to its poor pharmacokinetic properties, including the low permeability through the blood-brain barrier, and the rapid clearance from the gastrointestinal tract. Since poly(amino acid)s are advantageous for improving the beneficial bioactivities of conventional amino acids, poly(gamma-aminobutyric acid) (poly(GABA)) is a potential candidate for MDD therapy. Nevertheless, the non-water-soluble and non-dispersible characteristics of poly(GABA) render difficulty in administering its conventional forms in vitro/in vivo, thereby hindering its therapeutic applications. Therefore, this study proposes a new design for poly(GABA) in nanoparticle form, which is composed of the amphiphilic diblock copolymers of poly(GABA) and poly(ethylene glycol), providing a suitable formulation for medication applications. Herein, we report on a new orally deliverable poly(GABA)-based nanoparticles (NanoGABA) in aqueous media and their efficacy on mouse depression models. NanoGABA treatment efficiently attenuated depression-like symptoms as evidenced by behavioral tests (forced swimming tests and tail suspension tests) and stress biomarkers (corticosterone). These findings suggest that the newly designed poly(GABA)-based nanoparticles are a promising candidate for the treatment of depression. STATEMENT OF SIGNIFICANCE: This research is the first to report the preparation of poly(GABA)-based nanoparticles in aqueous conditions with beneficial physical properties to open the gate for medical and pharmaceutical applications of poly (GABA). It is also a pioneer in using poly(GABA)-based materials for major depressive disorder therapeutics in vivo. Oral administration of NanoGABA attenuates depressive-like symptoms by targeting the enteric nervous system possibly through modulation of the gut-brain axis pathways with negligible toxicity, suggesting that NanoGABA is a promising therapeutic agent for major depressive disorders.