Intelligent nanocatalyst mediated lysosomal ablation pathway to coordinate the amplification of tumor treatment

Abstract

The production of reactive oxygen species (ROS) is susceptible to external excitation or insufficient supply of related participants (e.g., hydrogen peroxide (H₂O₂) and sensitizer), liming ROS-driven tumor treatment. Additionally, the lysosomal retention effect severely hinders the utilization of ROS-based nanosystems and severely restricted the therapeutic effect of tumors. Therefore, first reported herein an intelligent nanocatalyst, TCPP-Cu@MnO_x ((Mn^II)₁(Mn^III)_2.1(Mn^IV)_2.6O_9.35), and proposed a programmed ROS amplification strategy to treat tumors. Initially, the acidity-unlocked nanocatalyst was voluntarily triggered to generate abundant singlet oxygen (¹O₂) to mediate acid lysosomal ablation to assist nanocatalyst escape and partially induce lysosomal death, a stage known as lysosome-driven therapy. More unexpectedly, the high-yielding production of ¹O₂ in acid condition (pH 5.0) was showed compared to neutral media (pH 7.4), with a difference of about 204 times between the two. Subsequently, the escaping nanocatalyst further activated H₂O₂-mediated ¹O₂ and hydroxyl radical (•OH) generation and glutathione (GSH) consumption for further accentuation tumor therapy efficiency, which is based on the Fenton-like reaction and Russell reaction mechanisms. Therefore, in this system, a program-activatable TCPP-Cu@MnO_x nanocatalyst, was proposed to efficiently destruct organelle-lysosome via ¹O₂ inducing, and stimulated H₂O₂ conversion into highly toxic ¹O₂ and •OH in cytoplasm, constituting an attractive method to overcome limitations of current ROS treatment.