Oxidative stress and reduced pH are involved in many inflammatory diseases. This study describes a nanoparticle-based system that is responsive to both oxidative stress and reduced pH in an inflammatory environment to effectively release its encapsulated curcumin, an immune-modulatory agent with potent anti-inflammatory and antioxidant capabilities. Because of the presence of Förster resonance energy transfer between curcumin and the carrier, this system also allowed us to monitor the intracellular release behavior. The curcumin released upon triggering could efficiently reduce the excess oxidants produced by the lipopolysaccharide (LPS)-stimulated macrophages. The feasibility of using the curcumin-loaded nanoparticles for anti-inflammatory applications was further validated in a mouse model with ankle inflammation induced by LPS. The results of these studies demonstrate that the proposed nanoparticle system is promising for treating oxidative stress-related diseases. © 2014 American Chemical Society.