Sono-triggered nanoamplifier mediates ferroptosis-immune regulation against bacterial pneumonia

In the post-pandemic era, multidrug-resistant (MDR) bacterial pneumonia has become a critical global health challenge due to its frequent evasion of conventional antibiotic therapies. Redox metabolic regulation therapy (RMRT), which targets pathological cells through reactive oxygen species (ROS)-mediated disruption of redox homeostasis, has emerged as a promising antibiotic-free approach with broad-spectrum efficacy and reduced resistance potential. In this study, we surprisingly discovered that tirapazamine (TPZ), a clinical hypoxia-activated anticancer prodrug, exhibits potent bacterial ferroptosis-inducing capability via multimodal metabolic interference, suggesting its repurposing potential for pneumonia treatment. To overcome pulmonary delivery limitations and enhance therapeutic performance, a self-reinforcing RMRT amplifier was engineered through supramolecular co-assembly of repurposed TPZ with natural sonosensitizer purpurin 18 (P18). Ultrasound-triggered P18 not only generates bactericidal ROS but also exacerbates infection-site hypoxia, thereby activating TPZ to initiate a ferroptosis cascade via dual mechanisms: ROS overproduction through hypoxia-specific bioactivation and extracellular Fe²⁺ influx potentiation. Notably, the resulting ferroptotic bacteria function as endogenous immunostimulants, subsequently trigger a cascade of immunological responses to establish an antimicrobial-favorable microenvironment. Such RMRT nanoamplifier presents a safe, efficient, and easily accessible strategy that synergizes ferroptosis-associated metabolic regulation and immune activation to combat MDR bacterial pneumonia.