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 and Yujun Song ()
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Zhiyong Liu: Nanjing University
Xiaowei Luan: Nanjing University
Qianglan Lu: Nanjing University
Shurong Qin: Nanjing University
Fei Zeng: Nanjing University
Zhi Li: Nanjing University
Bangshun He: Nanjing Medical University
Yujun Song: Nanjing University

Nature Communications, 2025, vol. 16, issue 1, 1-17

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-59590-9

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