Biomimetic mitochondria-targeted drug delivery system for the treatment of inflammatory bowel disease.

Mitochondria play a pivotal role in regulating inflammation and maintaining intestinal microenvironmental homeostasis during the progression of inflammatory bowel disease (IBD). However, to date, only a limited number of orally deliverable systems capable of mitochondrial targeting have been reported for IBD therapy. Existing approaches, such as charge- or ligand-dependent targeting peptides, were susceptible to physiological variations and exhibited suboptimal mitochondrial targeting efficiency. Here, we develop a hybrid membrane-based strategy incorporating two complementary functional modules: (i) M2 macrophage membranes, which enable inflammation-associated targeting; (ii) mitochondrial membranes, which facilitate mitochondrial targeting through membrane fusion. Encapsulated within a sodium alginate-carboxymethyl chitosan hydrogel, the melatonin-loaded hybrid membrane-coated nanoparticles (RC@MEL) arrive at colon following oral administration. Upon colonic release, RC@MEL are efficiently internalized by inflamed epithelial cells and macrophages, where the mitochondrial membrane coating facilitate fusion with mitochondria, achieving effective mitochondrial targeting. This subcellular delivery effectively scavenges mitochondrial ROS, promotes macrophage repolarization, enhances tight junction repair, and contributes to the restoration of gut microbiota homeostasis in both acute and chronic colitis models. Overall, this work establishes a mitochondria-targeting oral delivery strategy for IBD treatment and provides a generalizable design framework for subcellular-targeted therapeutics in inflammatory diseases.