Engineered EV-delivered H102 peptide provides multi-level neuroprotection against amyloid-beta toxicity in vitro.

Alzheimer's disease (AD) is a complex neurodegenerative condition characterized by amyloid-β (Aβ) aggregation, oxidative stress, and progressive neuronal dysfunction. Current therapeutic strategies face significant challenges, primarily due to inefficient delivery of bioactive molecules across the blood-brain barrier to target neuronal cells. Developing effective disease-modifying therapies requires innovative approaches to overcome these delivery hurdles and address the multi-faceted pathology of Aβ-induced neurotoxicity, which includes amyloidogenesis, apoptosis, and inflammation.

Researchers engineered extracellular vesicles (EVs) from NIH/3T3 cells expressing Lamp2b-RVG for neuronal targeting. The β-sheet breaker peptide H102 was conjugated to the EV surface via CP05-CD63 affinity binding. Successful peptide conjugation and vesicle integrity were confirmed using ATR-FTIR, SERS Raman spectroscopy, TEM, NTA, zeta potential, and EV marker profiling. Neuronal toxicity was induced in NGF-differentiated PC-12 cells with aggregated Aβ25-35. Primary endpoints assessed cell viability, membrane damage, intracellular reactive oxygen species (ROS) levels, and qPCR for APP, Bax, Sirt1, and Stat1 gene expression.