Coacervate protocells-mediated mitochondrial transplantation restores gut epithelial energetic homeostasis in ulcerative colitis

Ulcerative colitis (UC) is closely linked to mitochondrial dysfunction in intestinal epithelial cells, yet current therapies fail to correct underlying energy metabolism defects. While exogenous mitochondrial transplantation offers a promising strategy, its clinical translation is hindered by rapid loss of mitochondrial bioactivity ex vivo, poor delivery efficiency, and lysosomal degradation following cellular uptake. Here, we developed a biomimetic coacervate-based protocell system (HTP) via liquid-liquid phase separation of polyethylene glycol, tannic acid, and sodium hyaluronate for efficient encapsulation and delivery of functional mitochondria (HTP@Mito). HTP protocells preserved mitochondrial membrane potential and ATP synthesis capacity for up to 72 h in HBSS buffer at 37°C, far exceeding the viability of free mitochondria. Notably, HTP markedly enhanced intracellular delivery of isolated mitochondria via lipid-raft-mediated endocytosis. In a dextran sulfate sodium (DSS)-induced murine UC model, rectally administrating HTP@Mito achieved superior therapeutic efficacy via restoring ATP levels and mitochondrial membrane potential, scavenging reactive oxygen species (ROS). Furthermore, by reducing oxidative stress, HTP@Mito rescued lysosomal function and restored impaired autophagic flux, thereby promoting mitophagy to clear damaged mitochondria. HTP@Mito treatment also repaired intestinal epithelial tight junctions, restored goblet cell-derived mucus secretion, and rebalanced gut microbiota by increasing beneficial Lachnospiraceae while reducing pathogenic Escherichia-Shigella. Collectively, this work established a versatile, biomimetic organelle delivery platform that could correct mitochondrial energy deficiency in the intestinal epithelium, providing a framework for mitochondrial transplantation in ulcerative colitis.