Smart-responsive dual cross-linked chitooligosaccharide nanoparticles with high stability and ROS-triggered self-accelerating drug release for enhanced breast cancer therapy

The development of reactive oxygen species (ROS)-responsive nanodrug delivery systems faces critical challenges. Excessive cross-linking degree prevents complete degradation of nanocarriers under tumor microenvironment ROS levels, significantly compromising drug release efficiency. Conversely, insufficient cross-linking degree impairs the structural stability of nanoparticles, resulting in premature drug leakage during systemic administration. Herein, we present an innovative strategy for constructing dual cross-linked chitooligosaccharide nanoparticles (NPs) co-loaded with curcumin and glucose oxidase (GOx) to enhance structural stability. These engineered NPs can amplify intracellular ROS concentration through GOx-mediated catalytic conversion of glucose to H 2 O 2 , thereby establishing a ROS-triggered self-accelerating drug release nanosystem for enhanced tumor chemotherapy. In vitro studies have shown that the curcumin release behavior of CTCG NPs depends on the GOx encapsulated inside the nanoparticles. Compared with nanoparticles without GOx, CTCG NPs can effectively prevent the premature release of curcumin in a simulated normal physiological environment. The nanoparticles also showed significant anti-tumor effect and could effectively inhibit the proliferation of tumor cells in vivo . These results proved that CTCG NPs achieve controllable release of drugs through in situ production of ROS in the tumor microenvironment. This nanodrug delivery system shows promising potential for breast cancer therapy.