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

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.