Leber's hereditary optic neuropathy (LHON) is a rare inherited blindness caused by mutations in the mitochondrial DNA (mtDNA). The disorder is untreatable and tricky, as the existing chemotherapeutic agent Idebenone alleviates symptoms rather than overcoming the underlying cause. Although some studies have made progress on allotopic expression for LHON, in situ mitochondrial gene therapy remains challenging, which may simplify delivery procedures to be a promising therapeutic for LHON. LHON becomes more difficult to manage in the changed mitochondrial microenvironment, including increasing reactive oxygen species (ROS) and decreasing mitochondrial membrane potential (MMP). Herein, a pathologically responsive mitochondrial gene delivery vector named [triphenylphosphine‐terminated poly(sulfur‐containing thioketal undecafluorohexylamine histamine) and Ide‐terminated poly(sulfur‐containing thioketal undecafluorohexylamine histamine)] (TISUH) is reported to facilitate commendable in situ mitochondrial gene therapy for LHON. TISUH directly targets diseased mitochondria via triphenylphosphine and fluorination addressing the decreasing MMP. In addition, TISUH can be disassembled by high mitochondrial ROS levels to release functional genes for enhancing gene transfection efficiency and fundamentally correcting genetic abnormalities. In both traditional and gene‐mutation‐induced LHON mouse models, TISUH‐mediated gene therapy shows satisfactory curative effect through the sustained therapeutic protein expression in vivo. This work proposes a novel pathologically responsive in situ mitochondrial delivery platform and provides a promising approach for refractory LHON as well as other mtDNA mutated diseases treatments.
Mitochondrial heterogeneity above the biochemical threshold (~50% damaged mitochondria load) induces the symptom manifest of multiple mitochondrial diseases without effective treatment. However, current mitochondria-targeted therapies related to mitochondrial heterogeneity regulation have yielded unsatisfactory clinical incomes due to the risk of damaged mitochondria carryover and the imbalance of mitochondrial homeostasis. Here, we show that engineered mitochondria (Mitochondria-Lipo@mParkin, MLPers) constructed by adhesion of mitophagy-mediated liposomes to the surface of exogenous mitochondria can supply healthy mitochondria via exogenous mitochondria and both remove damaged mitochondria via enhanced mitophagy. MLPers decrease the high level of mitochondrial heterogeneity to less than 30% which is obviously lower than their biochemical threshold, and lead to the reversion of disease-related phenotypes in two mouse models of tricky mitochondrial diseases (Leber’s hereditary optic neuropathy and idiopathic pulmonary fibrosis). The surface adhesion-engineered mitochondria are powerful tools for maintaining homeostasis of mitochondrial pool and offer a translational approach for pan-mitochondrial disease therapies.
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