Work

13-Methylpalmatine liposome targeted binding to Armcx4 to restore mitochondrial function and improve vascular dementia

Year: 2026

Type: article

Abstract: Vascular dementia (VD) is the second most common type of dementia after Alzheimer’s disease, accounting for 15%-20% of all dementia cases. Its incidence continues to rise with the aging of the population. In 2021, there were approximately 56.9 million dementia patients worldwide, and this number is projected to exceed 137 million by 2050, imposing a heavy burden on patients’ families and the medical system. Currently, there are no specific drugs available for the treatment of this disease in clinical practice. From the TCMSP database, the dominant monomer palmatine (Pal) was selected from 48 individual molecules. However, its low bioavailability limited its application. By introducing a methyl group at the C-13 position based on the magic methyl effect, the resulting monomer 13-methylpalmatine (13MP) significantly outperformed Pal in terms of drug activity and molecular docking. We established 13MP as the core active compound. Subsequently, we fabricated an angiopep-2-modified brain-targeted liposomal delivery system (13MP-LIP-A) via thin‑film hydration. The system exhibited uniform particle size and favorable stability. The results showed that angiopep-2 modification significantly enhanced cellular uptake in HT22 cells and improved brain‑targeted distribution in vivo, effectively overcoming the bioavailability limitations of 13MP. The formulation alleviated oxidative stress, preserved mitochondrial function, and upregulated the expression of neurotrophic factors in vitro. In a VD mouse model, 13MP-LIP-A ameliorated cognitive deficits, restored cerebral blood flow, and attenuated neuronal pathology. Mechanistically, cross‑species transcriptomic analysis identified Armcx4 as a key mitochondrial‑associated target, and 13MP-LIP-A reversed its pathological downregulation. Knockdown of Armcx4 abrogated the protective effects on mitochondrial dynamics and function, suggesting that Armcx4 is an important mediator of the therapeutic response. In conclusion, this study successfully developed a liposome-based formulation that represents a promising preclinical candidate for VD intervention. The formulation exerts neuroprotective effects, with Armcx4 identified as a key contributor to the observed mitochondrial regulation, providing a new experimental basis for further mechanistic and translational investigation.

Source: Journal of Nanobiotechnology

DOI: 10.1186/s12951-026-04963-5