Lactoferrin-driven delivery of Kaixinsan nanomedicine for Alzheimer's disease neuroprotection: Mechanistic insights from bioinformatics and multi-target validation.

Alzheimer's disease (AD) is a common neurodegenerative disorder characterised by neurapoptosis and neuroinflammation-induced neuronal damage. However, the exact pathogenic mechanism of AD is still controversial, and the existing treatment methods are only effective for the early stage of the disease. Kaixinsan (KXS), a classic anti-amnestic traditional Chinese medicine, can effectively reduce oxidative stress and provide neuroprotection to the brain, but the exact molecular mechanism remains unclear. Herein, we synthesised a biomimetic KXS-delivery system (LTF@GO-PEG/KXS, LGPK), which significantly enhanced the blood-brain barrier (BBB) penetration efficiency was significantly improved, attributed to lactoferrin (LTF)-mediated receptor binding. LGPK exhibits excellent neuroprotection and repolarizes BV2 microglia from pro-inflammatory to anti-inflammatory phenotypes. Further bioinformatics analysis and western blot results indicated that LGPK could inhibit the progression of AD by inhibiting the production of amyloid precursor protein (APP) and hyperphosphorylated Tau (p-Tau), and downregulating TNF/NF-κB signalling pathways. In vivo studies using a transgenic Caenorhabditis elegans strain confirmed that LGPK both suppresses Aβ fibrillogenesis and attenuates oxidative stress, thereby highlighting its potential as a combination therapy for AD. Mechanistic investigations indicated that these neuroprotective effects were mediated through the suppression of the TNF/NF-κB signalling pathway, along with profound alterations in alternative splicing (AS) events. Collectively, these findings highlight LGPK as a promising multi-target nanomedicine for AD treatment by enhancing brain-targeted delivery and exerting combined anti-neuroapoptosis and anti-inflammatory.