Tetracycline-loaded nanomotors target neutrophil activation and oxidative stress in acute lung injury

Acute lung injury (ALI) has high mortality, underscoring the urgent need for effective therapies. Excessive inflammation, mainly driven by neutrophil activation and caspase-1-mediated IL-1β/IL-18 release, along with oxidative stress, plays a pivotal role in ALI progression. Tetracycline (TH) has shown promise in suppressing caspase-1-inflammasome signaling, and its therapeutic efficacy could be further enhanced through targeted delivery. Here, we developed a nitric oxide (NO)-driven nanomotor for reactive oxygen species (ROS)-responsive TH delivery (PMA@TH), enabling precise TH delivery to inflammatory lung tissues. Upon intratracheal administration, PMA@TH migrates to injury sites with high ROS concentrations to achieve precise drug release and the generated NO further enhances tissue penetration. The nanomotor not only inhibits neutrophil infiltration but also promotes macrophage M2 polarization, mitigating both local and systemic inflammation. Transcriptomic analysis further confirmed the dual anti-inflammatory and antioxidant effects of PMA@TH. This strategy demonstrates superior therapeutic outcomes in ALI models, offering a promising nanomedicine for clinical translation.