Construction, characterization, and antidepressant application of blood brain barrier-targeted Mahonia bealei monomer nanoparticles

Colloids Surf B Biointerfaces. 2025 Aug 7;256(Pt 2):115015. doi: 10.1016/j.colsurfb.2025.115015. Online ahead of print.

ABSTRACT

This study aimed to develop Mahonia bealei alkaloid (MA)-loaded nanoparticles (NPs) targeting the blood-brain barrier (BBB) for the treatment of depression. The MA@NPs were prepared via self-assembly using transferrin-modified chitosan-N, O-carboxymethyl chitosan (NOCMS-CS-Tf) as the carrier. Formulation optimization yielded uniform MA@NPs (∼192 nm, +29 mV) with a drug loading of ∼16 % and encapsulation efficiency of ∼80 %. Transmission electron microscopy (TEM) and scanning electron microscopy (SEM) revealed spherical MA@NPs with an average size of ∼55 nm under TEM, rough and porous surfaces, and good dispersibility. X-ray diffraction (XRD) analysis showed that the MA@NPs exhibited amorphous characteristics with reduced crystallinity after MA loading, while Fourier transform infrared spectroscopy (FTIR) confirmed successful MA encapsulation via hydrogen bonding and intermolecular interactions. The MA@NPs remained stable for over one month at 4 °C. In vitro release assays showed a sustained-release profile under conditions mimicking the depressive state. Consistently, in vivo fluorescence imaging indicated prolonged systemic retention, corroborating the sustained-release behavior of the MA@NPs. Cellular uptake experiments indicated enhanced BBB-targeting ability of MA@NPs especially under conditions of cellular stress or damage. Compared to free MA, the MA@NPs significantly alleviated lipopolysaccharide (LPS)-induced neuroinflammation in BV2 microglial cells and corticosterone (CORT)-induced neuronal damage in PC12 cells. In vivo, superior anti-neuroinflammatory effects compared to free MA were demonstrated in an LPS-induced mouse model of depression. Network pharmacology analysis, supported by qRT-PCR validation, revealed that both MA and MA@NPs activated the cAMP signaling pathway by upregulating the mRNA expression of protein kinase A (PKA), cAMP response element-binding protein (CREB), and brain-derived neurotrophic factor (BDNF). In conclusion, MA@NPs enhance the antidepressant efficacy of MA through sustained drug release, targeted brain accumulation, and modulation of neuroinflammation and neuroplasticity-related pathways.

PMID:40818157 | DOI:10.1016/j.colsurfb.2025.115015