Gastric Acid‐Responsive ROS Nanogenerators for Effective Treatment of Helicobacter pylori Infection without Disrupting Homeostasis of Intestinal Flora

Helicobacter pylori (H. pylori) has infected more than half of the world's population, and is the major cause of gastric cancer. The efficacy of standard antibiotic‐based triple therapy is declining due to drug resistance development. Herein, a pH‐responsive reactive oxygen species (ROS) nanogenerator (Fe‐HMME@DHA@MPN) composed of acid‐responsive metal polyphenol network (MPN) shell and mesoporous metal‐organic nanostructure core [Fe‐HMME (hematoporphyrin monomethyl ether, sonosensitizer)] loaded with dihydroartemisinin (DHA) is reported. These nanoparticles generate more ROS singlet oxygen than sonosensitizer HMME under ultrasonication, and this sonodynamic process is fueled by oxygen generated through Fenton/Fenton‐like reactions of the degraded product in gastric acid Fe (II) and hydrogen peroxide (H(2)O(2)) in the infection microenvironment. The encapsulated DHA, as a hydroperoxide source, is found to enhance the peroxidase‐like activity of the Fe‐HMME@DHA@MPN to generate ROS hydroxyl radical, beneficial for the microenvironment without sufficient H(2)O(2). In vitro experiments demonstrate that the ROS nanogenerators are capable of killing multidrug‐resistant H. pylori and removing biofilm, and ROS nanogenerators show high therapeutic efficacy in a H. pylori infection mouse model. Unlike the triple therapy, the nanogenerators display negligible side effects toward the normal gut microbiota. Taken together, these self‐enhanced ROS nanogenerators have a great potential for treatment of H. pylori infection.