Polydopamine Modified with Brain Targeting Peptide Rabies Virus Glycoprotein for Treatment of Alzheimer’s Disease by Inhibiting Oxidative Stress and Inflammatory Response

Heling Chu,1,* Yihao Sun,2,* Chuyi Huang,3,* Lei Wang,4 Qihao Guo,1,* Lixian Jiang5,6,* 1Department of Gerontology, Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China; 2Department of General Practice, Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China; 3Health Management Center, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, People’s Republic of China; 4Department of Orthopedic Surgery, Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China; 5Shanghai Key Laboratory of Neuro-Ultrasound for Diagnosis and Treatment, Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China; 6Department of Ultrasound in Medicine, Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China*These authors contributed equally to this workCorrespondence: Lixian Jiang, Shanghai Key Laboratory of Neuro-Ultrasound for Diagnosis and Treatment, Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, No. 600, Yishan Road, Shanghai, 200233, People’s Republic of China, Email [email protected] Qihao Guo, Department of Gerontology, Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, No. 600, Yishan Road, Shanghai, 200233, People’s Republic of China, Email [email protected]: Polydopamine (PDA) has been recognized as an antioxidant and anti-inflammatory agent. However, the difficulty to cross blood-brain barrier (BBB) limits PDA’s neuroprotective effects in the brain. Here, we aimed to construct PDA-rabies virus glycoprotein (RVG) by modifying the RVG29 polypeptide on PDA nanoparticles (NPs) and investigate whether PDA-RVG improved the cognitive function and pathology of Alzheimer’s Disease (AD) by inhibiting oxidative stress and inflammatory response.Methods: We prepared and characterized PDA NPs and tested whether PDA improved AD pathology in APP/PS1 mice. To facilitate PDA’s penetration across BBB, we modified RVG29 on PDA and examined its brain-specific targeting ability and biocompatibility. We further tested the effects of PDA-RVG on oxidative stress, inflammatory response and ferroptosis in both in vitro and in vivo AD models.Results: PDA demonstrated robust reactive oxygen species (ROS)-scavenging activity and effectively reduced Aβ deposition and the expression of APP and PS1 in APP/PS1 mice. PDA-RVG successfully crossed BBB in an in vitro BBB model. Meanwhile, compared with PDA, PDA-RVG intravenous injection exhibited good brain-specific targeting ability. Moreover, the hematological analysis revealed no significant differences between the PDA-RVG and control groups. In the in vitro AD experiment, PDA-RVG reduced ROS, inducible nitric oxide synthase, and pro-inflammatory cytokines levels in BV2 cells. Besides, PDA-RVG decreased ROS and apoptosis, while increased glutathione peroxidase4 (GPX4) and the viability of PC12 cells. More importantly, intravenous delivery of PDA-RVG improved cognitive function assessed by Morris water maze, and upregulated the ferroptosis-protective proteins Ferritin Heavy Chain 1 and GPX4 expression, while PDA alone did not lead to cognitive improvement.Conclusion: PDA reduces AD pathology, which is possibly attributed to its ability to scavenge ROS, ameliorate the inflammatory microenvironment and inhibit ferroptosis. Intravenous delivery of PDA-RVG has good brain-specific targeting ability and biocompatibility, and improves cognitive function in AD mice. This study provides a safe, effective, and promising therapeutic strategy for AD via oxidative stress-associated target.Keywords: Alzheimer’s disease, polydopamine, PDA-RVG, oxidative stress, neuroinflammation, ferroptosis