Mutant superoxide dismutase 1-catalyzed hydrogen therapy for amyotrophic lateral sclerosis achieved by intercepting oxidative stress–neuroinflammation crosstalk

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive motor neuron degeneration in the brain and spinal cord, with mutant superoxide dismutase 1 (SOD1) induced oxidative stress and neuroinflammation as key pathogenic drivers. Here, we uncover that mutant SOD1 is both a Fenton-like agent able for catalytical generation of ·OH and a hydrogenation catalyst for H 2 scavenging reactive oxygen species. To enhance the bioavailability of H 2 , we develop an orally administered Mg 2 Si nanosheets based feed for sustained release of high-amount H 2 . On an ALS model of hSOD1 G93A transgenic mice, Mg 2 Si feed remarkably delays ALS progression, improves the motor performance of ALS mice, and extends their lifespan. Histopathologically, oral Mg 2 Si treatment ameliorates motor neuron degeneration, misfolded SOD1 aggregation and reactive gliosis in spinal cord, while protecting neuromuscular junctions and ameliorating muscle atrophy during disease progression. Transcriptomic analysis demonstrates the H 2 -mediated down-regulation of both oxidative stress and neuroinflammatory pathways in response to the suppression of NLRP3 inflammasome activation. The proposed strategy of catalyzed hydrogen therapy offers an inspiration for metalloproteases-related neurodegenerative diseases treatment. Statement of Significance Amyotrophic lateral sclerosis (ALS) is an incurable and devastating neurodegenerative disease lacking effective clinical interventions. Although hydrogen gas (H 2 ) exhibits promising neuroprotective potential, conventional H 2 therapy is severely limited by unstable and transient H 2 release, failing to sustain long-term treatment requirements for chronic ALS pathogenesis. To overcome this bottleneck, we engineer oral administrable Mg 2 Si nanosheets that enable sustained H 2 release via gastrointestinal retention, achieving stable long-term hydrogen supplementation in vivo . Mechanistically, Mg 2 Si-derived H 2 efficiently eliminates excess free radicals triggered by toxic mutant SOD1, and further disrupts the pathological crosstalk between oxidative stress and neuroinflammation in ALS. In transgenic ALS mice, dietary Mg 2 Si intervention markedly ameliorates motor dysfunction and effectively delays disease progression. Collectively, this study firstly applies Mg 2 Si nanomaterial-based sustained hydrogen therapy for ALS treatment, establishes a novel gastrointestinal hydrogen delivery strategy, and provides an innovative and clinically translatable paradigm for the design of hydrogen delivery systems against neurodegenerative disorders. Download: Download high-res image (244KB) Download: Download full-size image