Engineered Metal-Organic Frameworks Preserve Mitochondrial Bioenergetics at Micromolar Concentrations

Abstract Metal-Organic Frameworks (MOFs) are emerging as versatile materials for bio-interfaces due to their structural tunability and ability to integrate with biological systems. Among them, the Zeolitic Imidazolate Framework ZIF-8 is widely investigated as a carrier for the delivery of therapeutic agents owing to its chemical stability, porous architecture, and biocompatibility. Extending these strategies to complex biological substrates is particularly relevant for therapeutic applications. In this context, mitochondria represent key targets, as they regulate cellular metabolism and their dysfunction underlies numerous mitochondrial diseases, thereby stimulating growing interest in mitochondrial transplantation as a potential therapeutic approach. Here, we investigate the one-pot, in-situ formation of ZIF-8 coatings on isolated mitochondria under physiological conditions using mild micromolar precursor concentrations to minimize mitochondrial perturbation during the self-assembly process. Structural characterization and bioenergetic analyses confirm the formation of MITO@ZIF-8 and the preservation of mitochondrial respiratory competence. Transplantation of MITO@ZIF-8 into Mouse Embryonic Fibroblasts (MEFs) increases cellular respiratory capacity without affecting cell viability, indicating that the coating is biocompatible and does not impair mitochondrial uptake. These results provide a safe platform for the further engineering of delivery systems aimed at enhancing internalization efficiency in mitochondrial transplantation therapeutics.