2. Academic Validation
  3. Biomimetic ferritin nanocages for synergistic co-delivery of metformin and rapamycin restore neurodevelopmental homeostasis in autism spectrum disorders

Biomimetic ferritin nanocages for synergistic co-delivery of metformin and rapamycin restore neurodevelopmental homeostasis in autism spectrum disorders

  • J Nanobiotechnology. 2025 Oct 14;23(1):670. doi: 10.1186/s12951-025-03760-w.
Yizhe Shen # 1,  Lele Yu # 2,  Liujiao Wang 1,  Jilu Jin 1,  Cheng Yu 3,  Yuan Fan 2,  Yue Lang 1,  Huashan Xu 1,  Byron C Jones 4,  Yishi Liu 3,  Jiaying Wu 1,  Siyuan Gao 1,  Fuxue Chen 5,  Shini Feng 6
Affiliations

Affiliations

  • 1 School of Life Sciences, Shanghai University, 99 Shangda Road, Shanghai China, 200444, P. R. China.
  • 2 School of Environmental and Chemical Engineering, Shanghai University, 99 Shangda Road, Shanghai China, 200444, P. R. China.
  • 3 Key Laboratory of Carbohydrate Chemistry and Biotechnology, School of Biotechnology, Ministry of Education, Jiangnan University, Wuxi, 214122, Jiangsu, China.
  • 4 Department of Genetics, Genomics and Informatics, University of Tennessee Health Science Center, Memphis, USA.
  • 5 School of Life Sciences, Shanghai University, 99 Shangda Road, Shanghai China, 200444, P. R. China. chenfuxue@staff.shu.edu.cn.
  • 6 School of Life Sciences, Shanghai University, 99 Shangda Road, Shanghai China, 200444, P. R. China. fengshini@shu.edu.cn.
  • # Contributed equally.
PMID: 41083985 DOI: 10.1186/s12951-025-03760-w
Abstract

Autism spectrum disorder (ASD) is a multifactorial neurodevelopmental disorder with limited treatment options, largely due to its complex etiology and the inadequate delivery of therapeutics to the central nervous system. Herein, we report a novel biomimetic nanocomposite, HFn@M/R, designed for the synergistic co-delivery of metformin (Met) and rapamycin (Rapa) to restore neurodevelopmental homeostasis in ASD. Heavy-chain ferritin (HFn) nanocages, produced via an Escherichia coli expression system, were employed as a dual-drug carrier owing to their high drug loading capacity and intrinsic blood-brain barrier permeability via Transferrin Receptor 1 targeting. Comprehensive physicochemical characterization confirmed structural integrity, optimal drug loading, and redox/pH-responsive release under pathological conditions. In neuronal models, HFn@M/R restored mitochondrial membrane potential, enhanced AMPK-CREB-BDNF signaling, and suppressed mTOR hyperactivation and autophagic blockade. In a valproic acid-induced rat model of ASD, HFn@M/R achieved robust brain accumulation, ameliorated behavioral deficits, and normalized hippocampal electroencephalogram patterns. Transcriptomic analyses further revealed that HFn@M/R modulated key neurodevelopmental, metabolic, and immune pathways, underscoring its capacity to orchestrate a multi-target therapeutic network. Collectively, our findings establish HFn@M/R as a promising precision nanomedicine platform for ASD treatment, with potential applicability to a broad range of neurodevelopmental and neuroinflammatory disorders.

Keywords

AMPK/mTOR signaling pathways; Autism spectrum disorder; Heavy-chain ferritin nanocages; Mitochondrial dysfunction rescue; Neuroinflammation.

Figures
Products