A biomimetic multienzyme‑mimetic Prussian blue nanozyme for catalytic ROS neutralization and macrophage reprogramming in photoacoustic imaging‑guided immunotherapy of acute lung injury

Acute lung injury (ALI) is a life‑threatening respiratory disease that lacks precise diagnostic tools and specific therapeutic interventions, highlighting an urgent need for theranostic strategies. Here, we developed a biomimetic multienzyme‑mimetic Prussian blue nanozyme (MM@HMPB/Sim) that couples catalytic ROS neutralization with macrophage reprogramming for photoacoustic (PA) imaging‑guided immunotherapy of ALI. The nanoplatform was constructed by cloaking simvastatin (Sim)‑loaded hollow mesoporous Prussian blue (HMPB) metal–organic framework (MOF) nanozyme with a native macrophage membrane (MM). The HMPB core exhibited catalase (CAT)‑, peroxidase (POD)‑, and superoxide dismutase (SOD)‑like activities, enabling cascade catalytic scavenging of reactive oxygen species (ROS). MM@HMPB/Sim efficiently scavenged ROS, alleviated oxidative cellular damage, promoted M1-to-M2 macrophage repolarization, and inhibited monocyte adhesion to inflamed endothelium via competitive receptor engagement. Mechanistically, the HMPB core appeared to upregulate NRF2-dependent antioxidant responses, while simvastatin seemed to enhance AMPKα1-mediated metabolic reprogramming. Their combination was associated with synergistic restoration of the PPARα/AMPKα1/NRF2 axis and suppression of NF-κB p65, correlating with reduced Th17 differentiation and IL-17A production, which may have facilitated a shift toward an M2-like phenotype. Together with MM-mediated inhibition of immune cell infiltration, these effects were accompanied by improved pulmonary immune homeostasis and attenuated lung injury. The nanozyme also displayed favorable biocompatibility and gradual in vivo clearance. This biomimetic multienzyme‑mimetic nanozyme offers a safe, PA imaging‑guided catalytic immunotherapy that integrates ROS neutralization with synergistic metabolic and antioxidant pathway modulation to resolve ALI, holding translational potential for ROS-driven inflammatory lung diseases.