Extending dual-targeting upper-limit in liposomal delivery of lithospermic acid B for Alzheimer's mitochondrial revitalization

Mitochondrial dysfunction is a pivotal event in Alzheimer's disease (AD) pathogenesis. Lithospermic acid B (LA) has shown promise in safeguarding mitochondria, yet the underlying mechanism remains elusive. Here, we present evidence that LA rejuvenated AD -related mitochondrial pool by co -activating mitophagy and mitochondria biogenesis via PINK1/LC3B/P62 and PGC-1 alpha/Nrf2. To advance in vivo application, hydrophilic LA was encapsulated in liposome (MT-LIP@LA) composed of D-mannosamine-cholesterol/DSPE-PEG2000-Tet1/lecithin (molar ratio, 3:0.3:10) for cascaded brain -neuron targeting. MT -LIP demonstrated 4.3 -fold enhanced brain accumulation (2.57%dose/g-brain) than LIP (0.60%dose/g-brain) and precisely targeted neurons at AD lesion sites. Mechanism studies unraveled factors contributing to the preeminent brain targeting ability of MT -LIP: (1) high -density modified mannose efficiently binds to glucose transporter 1 (GLUT1) on blood -brain barrier (BBB); (2) prone to trafficking towards caveolin-Golgi pathway during transcytosis. This augmented therapeutic platform efficiently restored mitochondrial health, prevented neurodegeneration, and ameliorated memory deficits in 3 x Tg-AD transgenic mice. Our studies revealed the underlying pharmacological mechanism of LA and provided a concise but efficient platform for neuronal mitochondria quality control in vivo.