ROS-Triggered Self-Aggregation of a β-Elemene Olefin-Rich Nanoemulsion for Mitochondrial-Targeted Metabolic Reprogramming and Colitis Inflammation Alleviation.

Purpose: Inflammatory bowel disease (IBD) is a chronic condition driven by pro-inflammatory macrophages. Although natural compounds with carbon-carbon double bonds (C=C bonds), such as β‑elemene, exhibit anti-inflammatory properties, their precise subcellular targets and mechanisms remain elusive. This study aimed to develop a targeted nanomedicine to elucidate the anti-inflammatory mechanism of β‑elemene and establish a novel therapeutic strategy for colitis. Patients and Methods: We engineered a reactive oxygen species (ROS)-responsive β‑elemene nanoemulsion (ELE-NE) for targeted drug delivery. Its therapeutic efficacy and mechanism were evaluated in a murine model of dextran sulfate sodium (DSS)-induced colitis. A mitochondria-targeted, ROS-activatable near-infrared probe was also developed for in vivo imaging tracking of inflammatory foci and assessment of therapeutic efficacy. Results: In DSS-induced colitis mice, ELE-NE preferentially accumulated in inflamed colon tissue and effectively alleviated disease pathology. Mechanistically, upon reaching inflammatory macrophages, ELE-NE utilized the pathological ROS surge to undergo spatially confined aggregation at mitochondrial sites. This nano-aggregation directly disrupted the electron transport chain (ETC), potently suppressing oxidative phosphorylation and reprogramming cellular energy metabolism. Consequently, this mitochondria-focused metabolic intervention attenuated M1 macrophage polarization, reduced pro-inflammatory cytokine secretion. Conclusion: This is the first report demonstrating that β‑elemene acts via ROS‑triggered mitochondrial aggregation and metabolic reprogramming. We deciphered the mechanism of β-elemene, revealing that its olefinic (C=C) functional group enables bioresponsive mitochondrial aggregation and metabolic reprogramming, thereby proposing the concept of "olefinic drugs" as a distinct therapeutic class. Furthermore, we established a novel theranostic paradigm for treating inflammatory diseases using olefinic nanomedicines, enabled by a companion imaging tool for non‑invasive detection of inflammatory foci and dynamic monitoring of the treatment process.