Transferrin-Conjugated Melittin-Loaded L-Arginine-Coated Iron Oxide Nanoparticles for Mitigating Beta-Amyloid Pathology of the 5XFAD Mouse Brain

초록

Background Alzheimer’s disease (AD) is one of the most prevalent neurodegenerative diseases and a major contributor to dementia. Although the cause of this condition has been identified long ago as aberrant aggregations of amyloid and tau proteins, effective therapies for it remain elusive. The complexities of drug development for AD treatment are often compounded by the impermeable blood-brain barrier (BBB) and low-yield brain delivery. In addition, the use of high drug concentrations to overcome this challenge may entail side effects. Melittin, a component of bee venom, shows promise as an anti-neurodegenerative agent due to its anti-inflammatory properties. However, its cytotoxicity presents challenges. To address this, melittin-loaded nanoparticles were developed, aiming to mitigate toxicity while enhancing drug delivery across the BBB. Methods The study utilized 5XFAD model mice to investigate the effects of transferrin-conjugated melittin-loaded L-arginine-coated iron oxide nanoparticles (Tf-MeLioNs) on AD. Tf-MeLioNs were synthesized and characterized via EMs, MALDI-TOF and dynamic light scattering analysis. In vitro assays assessed cytotoxicity and hemolytic activity. Drug release and tissue staining were performed, followed by in vivo tracking of Tf-MeLioNs via Prussian Blue staining and IVIS. Immunofluorescence staining and Western blot analysis for amyloid metabolism and activation of glial cells were conducted to evaluate therapeutic effects. Results The study synthesized and characterized Tf-MeLioNs. Tf-MeLioNs demonstrated successful conjugation of transferrin, excellent cell viability, minimal hemolytic activity, and controlled drug release. In vivo, Tf-MeLioNs showed no toxicity and reduced amyloid plaques in 5XFAD mice hippocampi, potentially through modulation of amyloid regulation proteins and microglial activation. Conclusions This study suggested the potential of Tf-LioNs as a delivery platform and that of Tf-MeLioNs for ameliorating amyloid-related pathologies in AD, and provides a foundation for the use of Tf-MeLioNs as a promising AD treatment strategy.