Work

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

Year: 2026

Type: article

Abstract: 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.

Source: Bioactive Materials

DOI: 10.1016/j.bioactmat.2026.10.023