Mitochondria-targeted hybrid nanovesicles trigger immunogenic cell death and remodel tumor neutrophils for enhanced colorectal cancer immunotherapy

Abstract

Cancer immunotherapy has garnered significant attention for its ability to reinstate immune responses to eliminate cancer effectively. Among immune cells, neutrophils play a dual-edged sword role in cancer, and the selective activation of beneficial neutrophil populations and targeted inhibition of tumor-promoting neutrophils have shown significant potential in cancer therapy. Here, we developed a neutrophil mimic nanovehicle (Neutrosome) capable of targeting colorectal cancer mitochondria (MNeutrosome), which consists of active neutrophil membranes hybridized with mitochondria-targeting liposome loaded with β-Lapachone (Liposome@Lapa), which is proposed to induce immunogenic cell death (ICD) and modulate the immune microenvironment. Our findings demonstrate that MNeutrosome@Lapa selectively accumulates in colorectal cancer mitochondria and activates quinone oxidoreductase-1 (NQO1), leading to robust reactive oxygen species (ROS) production and subsequent cancer cell apoptosis. Notably, the unloaded MNeutrosome was shown to reduce neutrophil infiltration into tumor tissue, whereas MNeutrosome@Lapa reprogrammed tumor-associated neutrophils (TANs) from a pro-tumor N2 phenotype to an anti-tumor N1 phenotype, further contributing to immune modulation. Overall, MNeutrosome@Lapa demonstrated excellent biocompatibility and significant therapeutic efficacy and represents a promising therapeutic platform for CRC treatment.