Reduced organic nitrogen compounds dominate the toxicity of PM2.5 organics following internal exposure.

Atmospheric fine particulate matter (PM2.5) remains a major global health risk, with its associated health burden continuing to rise despite decades of pollution control efforts. Air pollution studies often focus on particle levels and known toxins, missing hidden organics that may drive serious health risks. Here, we conducted a comprehensive molecular and toxicological investigation of urban atmospheric particles, integrating nontargeted analysis of high-resolution mass spectrometry, protein adductomics-based internal exposure assessment, and multi-endpoint toxicity prediction. We find reduced organic nitrogen (RON) compounds as the predominant drivers of the toxicity of the internal exposed particle-bound organic fraction. RON account for 39% of total multi-organ toxicity, exceeding the 23% contribution from traditionally emphasized oxygenated organics. RON compounds exhibit strong binding affinity to human serum albumin, facilitating systemic distribution and toxic effects across respiratory, neurological, hepatic, renal, and hematological endpoints. Our findings identify RON as a key driver of organic PM2.5 toxicity via internal exposure pathways and highlight the urgent need to regulate reactive nitrogen species.