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

Scientists created a new treatment for autism using tiny protective capsules that carry two medicines (metformin and rapamycin) directly to the brain. When tested in rats with autism-like behaviors, this treatment improved their symptoms and brain activity patterns. The treatment worked by fixing problems with brain cell energy, improving important brain signals, and affecting genes related to brain development. This is early research and hasn't been tested in humans yet.

This preclinical study developed a novel nanotechnology platform (HFn@M/R) that combines two existing drugs, metformin and rapamycin, in ferritin nanocages for autism treatment. The researchers tested this system in laboratory neuronal models and a rat model of autism induced by valproic acid exposure. The nanocarrier successfully crossed the blood-brain barrier and delivered both drugs to brain tissue. In the rat model, treatment improved behavioral symptoms and normalized brain wave patterns.

Laboratory studies showed the treatment restored cellular energy processes, enhanced important brain signaling pathways (AMPK-CREB-BDNF), and reduced overactive mTOR signaling. Gene expression analysis revealed effects on neurodevelopment, metabolism, and immune pathways, suggesting multiple therapeutic mechanisms.

This nanotechnology approach represents a novel strategy for autism treatment by enabling targeted brain delivery of combination therapies. However, extensive preclinical safety studies and human clinical trials would be required before clinical application. The multi-target approach may address autism's complex pathophysiology more effectively than single-drug treatments.

Animal model study only; no human data available. Single autism model (valproic acid-induced) may not represent full spectrum of ASD. Sample sizes and specific methodological details not provided in abstract. Long-term safety and efficacy unknown.

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.