Reactive oxygen species responsive nanomotors for gene edited metabolic disruption and immunotherapy
Zhiyong Liu, Xiaowei Luan, Qianglan Lu, Shurong Qin, Fei Zeng, Zhi Li, Bangshun He, Yujun Song
Abstract
While gene-editing-based tumor therapy holds promise, conventional passive-diffusion vectors face limited penetration in dense solid tumors. Here, we developed a ROS-driven gene editing nanomotor (RDN@PL), which takes hemin as the core and encapsulates CRISPR/Cas9 plasmids targeting LDHA (A glycolysis key enzyme). In tumor microenvironments, RDN@PL consumes extracellular ROS to fuel self-diffusiophoresis, achieving higher intratumoral accumulation than passive particles. Upon internalization, heme oxygenase-1 (HO-1) degrades RDN@PL, releasing CO and plasmids. LDHA knockout suppresses glycolysis while CO elevates mitochondrial ROS, which triggers apoptosis by disrupting metabolism and enhancing immunity. Simultaneously, extracellular ROS depletion by non-internalized nanomotors reverses immunogenic cell death (ICD) inhibition, enhancing CD8+ T cell infiltration in tumor. The Janus nanomotor enables extracellular ROS scavenging and intracellular ROS increment via HO-1-responsive cargo release and gene editing. This multi-level intervention strategy demonstrates 93.9 % tumor growth suppression in solid tumor models, providing a blueprint for engineering intelligent nanovesicles in precision oncology. Nanomotor delivery has the potential to improve therapeutic outcomes. Here, the authors use the natural reactive oxygen species gradient in the tumour microenvironment to target delivery of CRISPR/Cas9 gene editing plasmids using reactive oxygen species responsive nanomotors for metabolic disruption and immunotherapy.