Abstract / Summary
Abstract Approved Alzheimer’s disease therapies fail to address the two drivers of cognitive decline: loss of BDNF-TrkB signalling and accumulation of hyperphosphorylated tau protein. We designed and evaluated an intranasal poly(lactic-co-glycolic acid) (PLGA) nanoparticle co-loading two small molecules − 7,8-Dihydroxyflavone, a TrkB agonist, and EF24, a curcumin analog that binds to tau. The design was evaluated across molecular docking, molecular dynamics, ADMET prediction, pharmacokinetic simulation, and nanoparticle synthesis and characterisation. Among four compounds tested, 7,8-Dihydroxyflavone showed the strongest predicted TrkB binding (ΔG = -9.079 kcal mol⁻¹), exceeding donepezil and memantine, while EF24 showed the strongest predicted tau binding (-5.068 kcal mol⁻¹) and comparable GSK-3β affinity to other compounds. Over 20 ns molecular dynamics simulations, both candidates remained stably bound to their targets (ligand RMSD ≤ 3.1 Å), whereas both approved drugs dissociated. Both compounds were predicted to be blood-brain-barrier permeant and drug-like, with predicted median lethal doses exceeding those of the approved comparators. Intranasal delivery increased predicted brain exposure over oral administration across all pharmacokinetic metrics. Nanoparticles synthesised across three batches were consistent in size, dispersity and surface charge, falling within published specifications for intranasal delivery (152 nm; polydispersity 0.21; zeta potential − 26 mV). These findings identify this approach as a mechanistically grounded candidate warranting further in-vitro and in-vivo validation.