Nikita Katila ^a,1, Ramesh Duwa ^a,1, Sunil Bhurtel ^b, Shristi Khanal ^b, Srijan Maharjan ^b, Jee-Heon Jeong ^c, Sooyeun Lee ^a,*, Dong-Young Choi ^b,*, Simmyung Yook ^a,*

^a College of Pharmacy, Keimyung University, 1095 Dalgubeol-daero, Dalseo-Gu, Daegu 42601, Republic of Korea ^b College of Pharmacy, Yeungnam University, 280 Daehak-Ro, Gyeongsan, Gyeongbuk 38541, Republic of Korea ^c Department of Precision Medicine, School of Medicine, Sungkyunkwan University, Suwon 16419, Republic of Korea

^* Corresponding authors.
¹ These authors contributed equally to this work.

Parkinson's disease (PD) is a debilitating neurodegenerative condition characterized by the loss of dopaminergic neurons within the substantia nigra. The specific molecular mechanisms through which PD-associated neuronal loss occurs remain unclear, and there is no available effective treatment against PD-related neurodegeneration. Resveratrol (RSV) has exhibited promising neuroprotective effects via antioxidant and anti-inflammatory activity. However, its poor bioavailability in the brain represents a challenge for its application in PD treatment. In this study, we synthesized RSV-loaded PLGA nanoparticles (RSV-PLGA-NPs) conjugated with lactoferrin (Lf) to enhance RSV diffusion into the brain and assessed whether this formulation improved the neuroprotective effects of RSV in experimental PD models. The Lf-conjugated RSV-PLGA-NPs (Lf-RSV-PLGA-NPs) exhibited enhanced internalization into SH-SY5Y and human brain microvascular endothelial cells as compared to RSV-PLGA-NPs and free RSV. Further, Lf-RSV-PLGA-NPs were more effective than RSV-PLGA-NPs and free RSV in attenuating the MPP+-induced generation of reactive oxygen species, reduction of mitochondrial membrane potential, and cell death. Importantly, Lf conjugation specifically increased the accumulation of RSV-PLGA-NPs in the brain as determined via bioluminescent imaging analyses. Our formulation substantially enhanced the neuroprotective effects of RSV in the MPTP-induced PD model. Hence, Lf-RSV-PLGA-NPs represent a promising tool for improving RSV bioavailability and neuroprotection within the brain.