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

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.