Glucosamine/chitosan blend surface-engineered rutin-loaded polymer/lipid hybrid nanoparticles for neuroprotection in induced schizophrenia model

The objective of this investigation is to enhance the bioavailability and therapeutic activity of a hydrophobic flavonoid rutin, with reported neuroprotective potential, by developing an innovative drug delivery system. Rutin-loaded polymer/lipid hybrid nanoparticles comprising polycaprolactone and Geleol™ or Captex® were developed. They were assessed for entrapment efficiency, size, and zeta potential. The selected formula (F4) comprised equal ratios of polycaprolactone and Geleol™, revealed nanoparticle size (226.9 ± 38 nm) and a high entrapment efficiency value (78.84 ± 6.1%). A glucosamine/chitosan hydrochloride blend was used as a functional coating of F4. The studied formulations improved the release profiles of rutin, which were 33.60 ± 3.1%, 64.76 ± 5.8%, and 59.12 ± 4.3% for rutin, F4, and CF4, respectively. The efficacy of free rutin and the selected formulations was assessed using cuprizone-induced schizophrenia in mice. Behavioral, biochemical, and histopathological investigations demonstrated the therapeutic potential of rutin, which enhanced brain myelin basic protein (MBP) and neuregulin 1 (NRG1) levels, thereby restoring myelination. Rutin also stabilized dopamine and glutamate pathways, alleviating cognitive and neurochemical imbalances characteristic of schizophrenia. The designed rutin-loaded formulation proved more effective than the free rutin, and the functionalized formulation outperformed the uncoated formula. Collectively, these results underscore the promise of this delivery system, while further assessments for pharmacokinetics, brain uptake, and clinical investigations remain essential to verify its translational potential.