An adeno-associated virus gene therapy strategy for anti-obesity treatment by nanocarrier-based delivery systems

作者：Li Li, Wang Wang, Rong Li, Jiayue Guo, Xulin Hu, Yu Pan, Taoyuan Zhang, Sensen Chi, Zili Gu, Gaohui Zhu, Qi Liu, Shuai Tan · 发表于：Journal of Nanobiotechnology · 年份：2025 · DOI：10.1186/s12951-025-03595-5 · 被引用次数：4 · 研究领域：Virus-based gene therapy research、Adipose Tissue and Metabolism、Pancreatic function and diabetes

Gut microbiota is increasingly recognized for its profound influence on host metabolism. However, the mechanisms underlying the distinct metabolic phenotype observed in germ-free (GF) mice are not fully understood. Here, the serum levels of metabolic hormones glucagon-like peptide-1 (GLP-1) and peptide YY (PYY) were shown with significant elevation in GF than the conventionally-raised (CONV-R) mice. Single-cell transcriptome analysis revealed that Secretogranin II (Scg2), with a known function in secretion control, was exclusively expressed in enteroendocrine cells (EECs). Scg2 transcript levels were significantly up-regulated in GF mice, positively correlated with enhanced GLP-1 and peptide PYY secretion. To examine the functional significance of Scg2 in hormone regulation, cross-linked nanoparticles capable of long-term adhesion to intestinal epithelium were designed, with AAV adsorbed within the cross-linked structure. This innovative design enhances its stability and retention in vivo, providing a robust platform for continuous and efficient gene delivery. We evidenced that over-expression of Scg2 via AAV-loaded nanocarriers in the colons of mice on high-fat diet or with the ob/ob genotype not only enhanced the secretion of GLP-1 and PYY but also mitigated weight gain in these mice by reducing their appetite. A multi-omics analysis reveals that Scg2 overexpression in the colon decreased hypothalamic inflammation and activated tryptophan metabolic pathways. Collectively, o...