A First-Aid Nanomedicine Endowed with Microenvironment Self-Adaptive Regulation Ability to Facilitate Acute Liver Failure Prophylaxis and Therapy

Acute liver failure (ALF) represents a life-threatening medical emergency with high mortality, yet limited treatment is available clinically. Here, we report albumin-biomineralized nonstoichiometric copper sulfide nanoparticles serving as first-aid nanomedicine to combat ALF, conceptualized as NanoAID. The NanoAID exhibits an electron-donor nanoantioxidant property to scavenge reactive oxygen species and concurrent anti-inflammatory capacity to reprogram pro-inflammatory M1 macrophages into anti-inflammatory M2-phenotype, thereby mitigating excessive oxidative and inflammatory stress in ALF lesions. More interestingly, we found Cu ions release under an in situ oxidative stress switch and the resulting H₂S gas generation by NanoAID degradation, which further enhance the biosynthesis of intrahepatic antioxidant enzyme SOD1 and the repolarization of M1-to-M2 macrophages, respectively, thereby self-reinforcing ALF therapy. Such microenvironment self-adaptive regulation confers NanoAID with effective prophylactic efficacy and significant ALF survival advantages over the FDA-approved <i>N</i>-acetyl cysteine in multiple animal models, extending the first-aid window to 6 h post APAP intoxication. Transcriptomics results reveal the molecular mechanisms of NanoAID by promoting antioxidative and inhibiting inflammatory pathways, underscoring its great potential as a next-generation first-aid nanomedicine for ALF management.