Nanocapsule-mediated sustained H2 release in the gut ameliorates metabolic dysfunction-associated fatty liver disease.

Metabolic dysfunction-associated fatty liver disease (MAFLD) is estimated to affect a quarter of all population and represents a major health threat to all societies. Yet, currently no approved pharmacological treatment is available for MAFLD. H2-rich water has recently been reported to reduce hepatic lipid accumulation in MAFLD patients but its efficacy is limited due to low H2 dosage. Increasing H2 dose may enhance its therapeutic effects but remains technically challenging. In this study, we designed and synthesized a hydrogen nanocapsule by encapsulating ammonia borane into hollow mesoporous silica nanoparticles to achieve ultrahigh and sustained H2 release in the gut. We then investigated its efficacy in treating early-stage MAFLD and other metabolic dysfunctions such as obesity and diabetes. The hydrogen nanocapsule attenuated both diet-induced and genetic mutation induced early-stage MAFLD, obesity, and diabetes in mice, without any tissue toxicity. Mechanistically, we discovered that sustained and ultrahigh H2 supply by hydrogen nanocapsule increased, among other species, the abundance of Akkermansia muciniphila, highlighting reshaped gut microbiota as a potential mechanism of H2 in treating metabolic dysfunctions. Moreover, hepatic transcriptome showed a reprogramed liver metabolism profile with reduced lipid synthesis and increased fatty acid metabolism.