Alzheimer’s disease (AD) is a neurodegenerative disorder resulting in debilitating dementia with progressive loss of motor functions. Genetic modulation of neurotrophic factors and apolipoprotein E (ApoE) have emerged as powerful strategies offering preventive and protective effect against AD pathophysiology. Brain derived neurotrophic factor (BDNF), apolipoprotein E2 (ApoE2) and vgf (non-acronymic) which play a major role in neuronal plasticity, synapse formation, amyloid-beta regulation and cognition, are found to be reduced in the brain of AD patients. However, delivery of such large polar proteins (BDNF, ApoE2 and vgf) across blood brain barrier (BBB) is one of the most challenging tasks. Therefore, in this study, we developed and optimized liposomal nanoparticles capable of delivering gene encoding for BDNF, ApoE2 and vgf to the brain in a targeted manner. These nanoparticles were surface modified with glucose transporter-1 targeting ligand (mannose) and various cell penetrating peptides to promote selective and enhanced delivery to brain. Dual-modified nanoparticles demonstrated homogenous size between 150-200 nm with positive zeta potential. These nanoparticles demonstrated ∼50% higher transport across in vitro BBB model and showed significantly higher transfection of encapsulated pDNA in bEnd.3 cells, primary astrocytes and neuronal cells. Surface functionalized nanoparticles also demonstrated significantly higher transport (∼7% of injected dose/gram of tissue) and gene transfection (1.5 - 2 times higher than baseline level) across BBB following single intravenous administration in C57BL/6 mice without any signs of toxicity. Furthermore, liposomal nanoparticles encapsulating pBDNF tested in early (6-months) and advanced stages (9-months) of transgenic APP/PS1 mouse model of AD showed good functional efficacy. The dual-modified nanoparticles enhanced BDNF expression by ~2 times and resulted in >40% (p<0.05) reduction in toxic amyloid-beta in 6- and 9- months old APP/PS1 mice brains compared to their age-matched untreated controls. Plaque load was reduced ~7 and ~3 times (p<0.05), respectively, whereas synaptic proteins, synaptophysin and PSD-95, were found to be increased by >90% (p<0.05) in both age groups of transgenic mice following BDNF treatment using dual-modified nanoparticles in comparison to their age-matched controls. Moreover, no untowardly adverse effects were observed throughout treatment, suggesting a safe and effective strategy for treatment of AD pathophysiology.