Disease‐Stage Synchronized Nanozyme Therapy for Polymicrobial Sepsis through Adaptive Catalytic and Immune Reprogramming

Vollständiger Abstract

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ABSTRACT Sepsis remains a leading cause of mortality because current therapies fail to address its dynamically evolving pathophysiology, in which infection, oxidative stress, and immune dysfunction emerge sequentially and interdependently. Here, we present a pH‐adaptive nanozyme platform (MICP@HG) that orchestrates stage‐specific antibacterial and immunomodulatory activities throughout sepsis progression. The platform integrates near‐infrared imaging, catalytic therapy, and immune regulation into a single construct. In acidic infectious microenvironments, the Cu–piceatannol shell exhibits peroxidase‐mimicking activity and induces cuproptosis‐like bacterial death through metabolic collapse and redox imbalance. As the microenvironment normalizes, the nanozyme shifts toward antioxidative and anti‐inflammatory functions via superoxide dismutase (SOD)‐ and catalase (CAT)‐like activities. Concurrently, the hyaluronic acid (HA)/β‐glucan coating facilitates infection‐targeted delivery and reprograms macrophages toward a reparative phenotype while restoring immune responsiveness. This dynamic functional transition enables efficient eradication of multidrug‐resistant bacteria, attenuation of systemic inflammation, and preservation of organ function, ultimately achieving complete survival in polymicrobial sepsis models. Notably, the platform also elicits a vaccine‐like trained immunity effect that confers protection against reinfection. This work establishes a paradigm for temporally programmed nanotherapy that aligns therapeutic function with disease progression, offering a precision strategy for the treatment of complex inflammatory disorders.