# Luteolin-Loaded TGN/RAP12 Dual-Peptide Functionalized Nanoparticles: Synergistic Enhancement of BBB Penetration and Microglia Targeting in Alzheimer’s Disease

## TL;DR

Researchers developed a nanoparticle delivery system to improve luteolin's ability to cross the blood-brain barrier and target microglia in Alzheimer’s disease.

## Contribution

A novel nanoparticle system combining RBC membrane coating and dual peptides enhances BBB penetration and microglia targeting for Alzheimer’s treatment.

## Key findings

- TGN/RAP12-RBC-NPs@Ltn significantly improved BBB permeability and microglia targeting.
- Encapsulated luteolin enhanced cognitive function and reduced mitochondrial dysfunction in AD mice.
- RBC membrane coating reduced macrophage phagocytosis and improved nanoparticle immune evasion.

## Abstract

Luteolin (Ltn), a natural flavonoid, effectively inhibits microglial activation in Alzheimer’s disease (AD) with promising therapeutic potential, but its efficacy is severely limited by the blood–brain barrier (BBB). To overcome this obstacle, this study prepared poly (lactic-co-glycolic acid) (PLGA) nanoparticles (NPs)—designated as TGN/RAP12-RBC-NPs@Ltn—which were coated with red blood cell membranes (RBCm) functionalized with two peptides, TGN (TGNYKALHPHN) and RAP12 (EAKIEKHNHYQK). The results demonstrated that TGN significantly enhanced BBB permeability, while RAP12 enabled effective targeting and delivery of TGN/RAP12-RBC-NPs@Ltn to microglial mitochondria in the brain. In addition, the presence of RBCm significantly inhibited the phagocytosis of NPs by macrophages, exerting a notable role in immune evasion. Meanwhile, the study confirmed that encapsulating Ltn within NPs significantly enhanced cognitive function in APP/PS1 mice, modulated the expression of key mitochondrial metabolic enzymes—pyruvate dehydrogenase (PDH) and its phosphorylated forms (pS232PDH, pS293PDH, pS300PDH)—in microglia, thereby ameliorating mitochondrial dysfunction and effectively regulating the neuroinflammatory environment in the mouse brain, and ultimately contributed to therapeutic efficacy. From this, it could be seen that TGN/RAP12-RBC-NPs@Ltn could significantly enhance the therapeutic effect of Ltn on AD, providing an effective treatment strategy for delaying the progression of AD.