Jaehoon Kim^a,1, Hyeji Um^a,1, Na Hee Kim^a, Dokyoung Kim^a,b,c,d,e,f

^aDepartment of Biomedical Science, Graduate School, Kyung Hee University, Seoul, 02447, Republic of Korea
^bMedical Research Center for Bioreaction to Reactive Oxygen Species and Biomedical Science Institute, Kyung Hee University, Seoul, 02447, Republic of Korea
^cDepartment of Anatomy and Neurobiology, College of Medicine, Kyung Hee University, Seoul, 02447, Republic of Korea
^dCenter for Converging Humanities, Kyung Hee University, Seoul, 02447, Republic of Korea
^eKHU-KIST Department of Converging Science and Technology, Kyung Hee University, Seoul, 02447, Republic of Korea
^fUC San Diego Materials Research Science and Engineering Center, 9500 Gilman Drive La Jolla, CA, 92093, USA

¹These authors contributed equally.
Corresponding author: Dokyoung Kim

There has been a lot of basic and clinical research on Alzheimer's disease (AD) over the last 100 years, but its mechanisms and treatments have not been fully clarified. Despite some controversies, the amyloid-beta hypothesis is one of the most widely accepted causes of AD. In this study, we disclose a new amyloid-beta plaque disaggregating agent and an AD brain-targeted delivery system using porous silicon nanoparticles (pSiNPs) as a therapeutic nano-platform to overcome AD. We hypothesized that the negatively charged sulfonic acid functional group could disaggregate plaques and construct a chemical library. As a result of the in vitro assay of amyloid plaques and library screening, we confirmed that 6-amino-2-naphthalenesulfonic acid (ANA) showed the highest efficacy for plaque disaggregation as a hit compound. To confirm the targeted delivery of ANA to the AD brain, a nano-platform was created using porous silicon nanoparticles (pSiNPs) with ANA loaded into the pore of pSiNPs and biotin-polyethylene glycol (PEG) surface functionalization. The resulting nano-formulation, named Biotin-CaCl2-ANA-pSiNPs (BCAP), delivered a large amount of ANA to the AD brain and ameliorated memory impairment of the AD mouse model through the disaggregation of amyloid plaques in the brain. This study presents a new bioactive small molecule for amyloid plaque disaggregation and its promising therapeutic nano-platform for AD brain-targeted delivery.