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.

Background: Mitochondrial dysfunction in microglia is an important pathogenic factor inducing the onset of Parkinson’s Disease (PD). To address this challenge, a novel hierarchical nano-delivery system was developed to deliver a PD therapeutic agent, wedelolactone (WED) to modulate mitochondrial dysfunction. Methods: The nano-delivery system (WED@RBCm-B6&RAP12-NPs) was coated with red blood membrane (RBCm) to avoid immune clearance and conjugated with the BBB-penetrating peptide CGHKAKGPRK (B6) and the microglia targeting peptide EAKIEKHNHYQK (RAP12). Results: The experimental results demonstrated that this novel nano-delivery system could increase its half-life in blood circulation effectively via evading immune recognition and clearance and enhanced its brain distribution by synergistic effect of B6 and RAP12. By specifically targeting microglia in PD mouse brain, the system increased pyruvate dehydrogenase (PDH) activity, leading to mitochondrial structural repair, reduced secretion of pro-inflammatory cytokines, and improved the inflammatory microenvironment. Conclusions: The result first designed and synthesis a dual targeting drug delivery system WED@RBCm-B6&RAP12-NPs which significantly alleviated mitochondrial dysfunction and warranted further study to develop therapeutic agent for PD treatment.