Multi-targeted ROS-responsive self-immolative nanoparticles for releasing hydrogen sulfide and in situ binding of...

Blast accidents are common in daily life and industrial settings and frequently result in acute lung injury (ALI), which may progress to respiratory failure in severe cases. Beyond the initial mechanical insult, dysregulated inflammatory responses and excessive reactive oxygen species (ROS) generation drive sustained ALI progression. However, current therapeutic strategies are limited by suboptimal efficacy and systemic side effects, highlighting an urgent need for more effective interventions. Herein, we develop a self-immolative, ROS-responsive nanoplatform (PPTCBR) for multi-targeted therapeutic intervention against blast-induced ALI. The nanoplatform is constructed from poly(ethylene glycol)-modified poly(L-lysine) incorporating ROS-cleavable thiocarbamate moieties. Under pathological high-ROS conditions, PPTCBR nanoparticles undergo self-immolative degradation, releasing carbonyl sulfide (COS), which is subsequently converted by endogenous carbonic anhydrase into hydrogen sulfide (H₂S) with potent anti-inflammatory and antioxidant activities. Concurrently, the resulting cationic polymer framework neutralizes cell-free DNA (cfDNA) and neutrophil extracellular traps (NETs), thereby interrupting inflammatory cascade amplification. Moreover, surface modification with RGD peptides enhances active targeting and retention in injured lung tissue. Systematic in vitro and in vivo studies demonstrate that PPTCBR nanoparticles exhibit excellent ROS responsiveness, favorable biocompatibility, and effective pulmonary accumulation, significantly alleviating blast-induced ALI and improving lung function. These findings present a pathology-responsive and multi-target nanotherapeutic strategy integrating immunomodulation for effective blast-induced ALI management. STATEMENT OF SIGNIFICANCE: 1. This work developed targeted ROS-responsive self-immolative nanoparticles to intelligently deliver H₂S for regulating the inflammatory microenvironment. 2. The nanoparticles enabled binding of cfDNA/NETs in situ at the site of inflammation after degradation. 3. The nanoparticles exhibited excellent therapeutic effects in blast induced ALI mice models. 4. The proposed multifunctional nanoparticles are a promising therapeutic strategy for inflammatory diseases.