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Abstract Parkinson’s disease (PD) is a progressive neurodegenerative disorder characterized by α-synuclein (α-syn) aggregation, neuroinflammation, and oxidative stress. Although intravenous immunoglobulin (IVIG) contains naturally occurring antibodies against α-syn oligomers, it has failed to demonstrate therapeutic efficacy in PD models, likely due to limited delivery across the blood-brain barrier (BBB). Enhancing BBB penetration of IVIG could therefore substantially improve its therapeutic potential in PD. Here, we developed a brain-targeted IVIG formulation (IVIGᴬ) by site-specifically conjugating Angiopep-2 (Ang-2) to the Fc glycan site (Asn297) of IVIG, enabling receptor-mediated transcytosis across the BBB via low-density lipoprotein receptor-related protein-1 (LRP1). Compared with unmodified IVIG, IVIGᴬ exhibited significantly enhanced brain accumulation. Moreover, systemic administration of IVIGᴬ markedly improved motor and cognitive performance in A53T α-syn transgenic mice by reducing phosphorylated α-syn aggregates, preserving dopaminergic neurons and synaptic integrity, and attenuating neuroinflammation, oxidative stress, and complement activation. These findings suggest that IVIGᴬ represents a promising immunotherapeutic agent with translational potential for the treatment of PD and other neurodegenerative disorders.
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