Drug delivery system targeting acid sphingomyelinase reduction in vascular endothelial and neuronal cells to restore autophagy in Alzheimer's therapy

Autophagy dysfunction is intimately involved in Alzheimer's disease (AD) pathogenesis, and restoring autophagy may alleviate pathology and improve cognition. Brain microvascular endothelial cells (BMECs) represent the primary source of acid sphingomyelinase (ASM), which inhibits neuronal autophagy. Suppressing ASM in BMECs can restore autophagy and potentially treat AD. To address this target, we developed a liposomal formulation (RVG-pSL@FIN/RSV) loaded with fingolimod (FIN) and rosuvastatin (RSV), and modified with rabies virus glycoprotein (RVG) peptide to target BMECs and neurons. Upon targeting BMECs, RVG-pSL@FIN/RSV releases FIN, which serves dual functions: inhibiting ASM production in BMECs and promoting transport across the blood-brain barrier (BBB). This transport enhancement facilitates subsequent passage of RVG-pSL@FIN/RSV across the BBB to target neurons, where FIN is released to inhibit both ASM and phosphorylated tau protein (p-Tau) production. Simultaneously, RSV is released within the neurons to restore autophagy, clearing accumulated p-Tau and amyloid-beta (Aβ) proteins while inhibiting Aβ aggregation. Our dual-targeting nanodelivery system modulates BMECs and neurons, inhibiting ASM activity while enhancing trans-BBB transport. RVG-pSL@FIN/RSV reduces BMEC-derived ASM in AD mice, restores autophagy, suppresses pathogenic protein accumulation, and improves cognition. This work presents a nanodelivery system targeting BMEC-derived ASM to restore autophagy as a potential therapeutic strategy for AD.