Bidirectional Amplification of Oxidative Stress via Mitochondria-Targeted Co-Delivery of Nanogolds and Chlorin e6 Using ROS-Responsive Organosilica Nanocarriers.

Abstract

Bidirectional amplification of oxidative stress within the mitochondria is essential to enhance photodynamic therapy (PDT), and efficient co-delivery of reducing agents and reactive oxygen species (ROS)-generating agents is critical for achieving this with minimal side effects. However, the absence of an effective platform for mitochondria-targeted co-delivery and spatially controlled tumor-specific therapy limits the potential applicability of this strategy. In this study, we developed an ROS-sensitive organosilica nanocarrier, encapsulating nanogold and introducing chlorin e6 (Ce6) and triphenylphosphine (TPP) through a one-pot sol-gel process. Following TPP-mediated mitochondria-targeted delivery, ROS generated by Ce6 under near-infrared (NIR) irradiation not only damaged the mitochondria but also disrupted the nanoparticles within the tumor, leading to the release of nanogold. These ultra-small nanogolds, due to their high surface area, exhibited enhanced glutathione scavenging capacity, which, in combination with ROS, synergistically amplified oxidative stress to overcome the high resistance of tumor cells. Both in vitro and in vivo experiments confirmed the effectiveness of this strategy, demonstrating efficient co-delivery, controlled drug release, spatially targeted oxidative stress amplification, and synergistic antitumor effects. Thus, we present a facile platform for the spatially controlled bidirectional amplification of oxidative stress with minimal side effects. STATEMENT OF SIGNIFICANCE: Mitochondrial oxidative stress involves both ROS generation and GSH depletion, indicating that bidirectional amplification is required for mitochondria-targeted antitumor therapy. However, most of existing strategies just focus on ROS generation, which limits the amplification level of oxidative stress. Thus, the mitochondria-targeted co-delivery of photodynamic agent and GSH scavenging agent is an effective approach to address this limitation. Besides, the lack of facile nanoplatform also hinders the application of strategies aimed at bidirectionally amplifying oxidative stress. In this study, we developed a facile nanoplatform for mitochondria-targeted co-delivery of the photodynamic agent Chlorin e6 and GSH scavenging agent nanogold using a ROS-responsive organosilica nanocarrier. This approach successfully achieved bidirectional amplification of oxidative stress, resulting in a synergistic antitumor effect with minimal side effects.