Bifunctional halloysite nanotube-based Ripk1 siRNA delivery system rescues cognitive impairment by targeting amyloid β plaques for clearance and reducing necrotic neurons in Alzheimer’s disease mice

Alzheimer's disease (AD) is exacerbated by abnormal accumulation of toxic β-amyloid (Aβ) aggregates and Aβ-mediated neuronal cell death. Currently, no effective drugs for AD treatment are mainly due to the blood–brain barrier hindrance, which limits the most drugs for application in AD treatment. Accumulating evidence suggests that increased levels of Ripk1 and enhancement of Ripk1-mediated neuronal necroptosis are known to play an important role in neuronal death in AD. Targeting Ripk1 by pharmacological or genetic inhibition of Ripk1 has been demonstrated to prevent neuronal necroptosis and improve memory deficits in AD mice models. Here, we showed that halloysite (HNTs), one of the nanoclays, absorbed Aβ and reduced toxic Aβ aggregate production by inhibiting fibril formation and promoting the clearance of Aβ plaques. We also presented evidence that RVG29, a brain-penetrating peptide, bound directly to Aβ species and inhibited Aβ aggregation. In addition, Ripk1 is more dramatically expressed around Aβ plaques than those far from plaques in the brain of AD mice. Therefore, we designed a novel Aβ plaque-targeted nanomedicine (SH-RVG/siRipk1) via functionalizing with RVG29 onto short HNTs (SH) and loading Ripk1 siRNA (siRipk1) into the lumen of SH to prevent siRipk1 degradation. As we expected, SH-RVG/siRipk1 not only reduced plaques and improved memory impairment but also rescued necrotic neuronal loss around plaques by reducing Ripk1 expression around plaques in AD mice. These findings indicate that SH-RVG/siRipk1 may be an effective strategy for the treatment of AD.