Reactive oxygen species (ROS) play an important role in the development of inflammatory bowel diseases. Superoxide dismutase (SOD) has a great therapeutic potential by scavenging superoxide that is one of ROS; however, in vivo application is limited especially when it is orally administered. SOD is easily degraded in vivo by the harsh conditions of gastrointestinal tract. Here, we design a zein-alginate based oral drug delivery system that protects SOD from the harsh conditions of gastrointestinal tract and releases it in the environment of the small intestine. SOD is encapsulated in zein-alginate nanoparticles (ZAN) via a phase separation method. We demonstrate that ZAN protect SOD from the harsh conditions of the stomach or small intestine condition. ZAN (200: 40) at the weight ratio of 200 mg zein to 40 mg of alginate releases SOD in a pH dependent manner, and it releases 90.8 +/- 1.2% of encapsulated SOD at pH 7.4 in 2 h, while only 11.4 +/- 0.4% of SOD was released at pH 1.3. The encapsulation efficiency of SOD in ZAN (200: 40) was 62.1 +/- 2.0%. SOD in ZAN (200: 40) reduced the intracellular ROS level and it saved 88.9 +/- 7.5% of Caco-2 cells from the toxic superoxide in 4 hours. Based on the results, zein-alginate based oral drug delivery systems will have numerous applications to drugs that are easily degradable in the harsh conditions of gastrointestinal tract. (C) 2016 Elsevier B.V. All rights reserved.