Antioxidant polymer nanoparticles ameliorate cancer cachexia via intestinal ROS scavenging.

Cancer cachexia affects approximately 80% of patients with advanced cancer, leading to anorexia, weight loss, and severe muscle wasting that negatively impacts survival. Despite its clinical significance, no effective therapies have been approved worldwide. Inflammatory cytokines, particularly interleukin-6 (IL-6), are known to play a key role in the pathogenesis of cachexia and represent promising therapeutic targets. In this study, we explored the role of intestinal oxidative stress in regulating systemic inflammation associated with cancer cachexia. We orally administered antioxidant polymer nanoparticles (siSMAPo(TN)), designed to localize in the intestinal lumen and selectively scavenge reactive oxygen species (ROS), to tumor-bearing cancer cachexia model mice. As a result, siSMAPo(TN) treatment suppressed plasma IL-6 elevation, mitigated muscle protein degradation signaling, and effectively prevented muscle atrophy. Notably, the intestinally localized action of antioxidant nanoparticles led to systemic therapeutic effects, thereby significantly alleviating cancer cachexia. These findings highlight that increased oxidative stress contributes to the systemic inflammatory cascade of cachexia, and demonstrate the therapeutic potential of intestinally acting antioxidant nanoparticles as a novel non-invasive strategy for cancer cachexia management.