bims-mitrat 2026-04-26 papers

Chem Biol Drug Des. 2026 Apr;107(4): e70296

Emerging Design Principles at the Forefront of Mitochondrial Transplantation Using Engineering Methodologies: Current Achievements and Future Directions.

Naoto Yoshinaga, Keiji Numata.

Mitochondrial transplantation has gathered much attention as therapeutics to improve multiple mitochondrial functions simultaneously. While the administration of naked mitochondria into the target tissue has demonstrated therapeutic outcomes sufficient to advance to clinical trials, there remain many limitations, including a low cellular uptake efficiency in the target tissue and dysfunction of the isolated mitochondria. To address these issues, engineering approaches have been developed to functionalize the isolated mitochondria. In this review, we focus on the three critical topics for efficient mitochondrial transplantation and outline emerging design rules and their limitations for each purpose: (i) tissue targeting, (ii) protection of mitochondria from external stresses, and (iii) improvement of cellular uptake efficiency. From these achievements, we also discuss the current limitations of mitochondrial transplantation and propose the future direction of the attractive therapeutic methodology.

Keywords: lipid; metal–organic framework; mitochondria transplantation; mitochondrial coating; peptide; polymer

DOI: https://doi.org/10.1111/cbdd.70296

Acta Physiol (Oxf). 2026 Jun;242(6): e70231

Mitochondrial Transplantation as a New Therapeutic Approach Against Cardiac and Renal Consequences in Male Rats With Myocardial Infarction.

María Cuesta-Corral, Alejandro Montoro-Garrido, Ana Romero-Miranda, Fabián Islas, Bunty Ramchandani, Ricardo Gredilla, Joaquín Fernández-Irigoyen, Enrique Santamaría, Beatriz Delgado-Valero, Sara Jiménez-González, Raquel Rodrigues Díez, María Luisa Nieto, Victoria Cachofeiro, Ernesto Martínez-Martínez.

AIM: Myocardial infarction (MI) is one of the leading causes of death worldwide. MI is associated with cardiac structural and functional alterations. Among these, cardiac fibrosis may be significantly influenced by mitochondrial dysfunction. We sought to evaluate whether the injection of functional mitochondria from healthy muscle could improve the detrimental consequences of MI.
METHODS: Male Wistar rats were submitted to MI through the ligature of the left anterior descending coronary artery. Animals subjected to a sham operation (the same surgical procedure without fastening of the suture that passes through the LAD) were included as a reference group (Sham). At the time of surgery, either vehicle (PBS) or isolated mitochondria (equivalent to 180 μg of mitochondrial protein in 75 μL of vehicle) were directly injected into the myocardium around the ligation to half of the animals in each group. Animals were sacrificed 4 weeks after both MI induction and the evaluation of cardiac and systolic functions.
RESULTS: Cardiac mitochondrial transplantation was able to prevent the decrease in systolic function and the development of cardiac fibrosis in MI rats. These beneficial effects were accompanied by a reduction in cardiac hypertrophy, oxidative stress, endoplasmic reticulum stress activation, and inflammatory markers. We also evaluated the effects of mitochondrial transplantation by a proteomic analysis. In addition, cardiac mitochondrial transplantation was able to prevent the development of renal alterations observed in MI rats.
CONCLUSIONS: The data reveal novel mechanisms of mitochondrial transplantation effects and emerge as a novel therapeutic strategy under chronic diseases such as MI.

Keywords: cardiac fibrosis; endoplasmic reticulum stress; inflammation; mitochondrial transplantation; myocardial infarction; oxidative stress; renal damage

DOI: https://doi.org/10.1111/apha.70231

Small Sci. 2026 Mar;6(3): e202500598

A Nanotube Injector for Cytoplasmic Transfer and Enhanced Mitochondrial Function.

Bingfu Liu, Zhuhang Dai, Bowen Zhang, Kazuhiro Oyama, Chenxi Li, Yukun Chen, Mingyin Cui, Takeo Miyake.

The intercellular transportation of molecules is crucial for regulating cell communication and function. However, the existing techniques for molecule transfer across cell barriers often cause cellular damage or have low transfer efficiencies. To address these limitations, this study proposes an innovative nanotube membrane-based injector (nanoinjector) system capable of extracting diverse cytoplasmic molecules from source cells and transferring them to target cells. The developed system demonstrates high efficiency, with over 95% viability and 90% transfer efficiency. Additionally, it enables mitochondrial transfer, which enhances cellular adenosine triphosphate (ATP) production by up to 25% within 24 h. This study explores the impact of intracellular content transport, enabled by this new tool, on cellular activities, with promising implications for cell surgery and therapy.

Keywords: adenosine triphosphate synthesis; mitochondria transfer; molecular delivery; nanotubes membrane

DOI: https://doi.org/10.1002/smsc.202500598

Bioact Mater. 2026 Sep;63 484-505

Polysaccharide-engineered mitochondria reprogram macrophages to resolve diabetic wound inflammation and promote repair.

Chenyan Yu, Qian Feng, Yuheng Liao, Meijun Tan, Yanzhi Zhao, Lang Chen, Wenqian Zhang, Chuanlu Lin, Ruiyin Zeng, Fawwaz Al-Smadi, Haochen Wang, Longyu Du, Xin Zhang, Ying Hu, Guodong Liu, Zhiyong Hou, Hang Xue, Guohui Liu.

Chronic diabetic wounds are characterized by persistent inflammation, defective resolution and impaired tissue regeneration, in which macrophage dysfunction and mitochondrial damage play central roles. Here, we developed a macrophage-targeted engineered mitochondrial transplantation system by coating adipose-derived stem cell (ADSC) mitochondria with triphenylphosphonium-modified konjac glucomannan (Mito-TPP-KGM). This design preserves mitochondrial membrane potential and ATP production while reducing ROS generation, and provides a mannose-rich corona for lectin receptor-related uptake. In RAW264.7 macrophages exposed to high glucose plus H2O2 or LPS, Mito-TPP-KGM is efficiently internalized, restores mitochondrial homeostasis, rebalances glycolysis and oxidative phosphorylation, and shifts inflammatory profiles toward a less inflammatory and more reparative phenotype. Engineered mitochondria also restore efferocytosis of apoptotic neutrophil-like cells and enhance the pro-angiogenic capacity of macrophage-conditioned media, thereby improving endothelial tube formation, migration and proliferation. Blocking experiments with mannan and anti-CD206/anti-DC-SIGN antibodies, together with species-specific mtDNA quantification, indicate that mannose-type lectin receptors contribute to the uptake and immunomodulatory effects of Mito-TPP-KGM. In a db/db mouse full-thickness wound model, local delivery of Mito-TPP-KGM promotes wound repair, improves histological healing, reduces oxidative damage, enhances angiogenesis, and modulates wound macrophage phenotype, leading to accelerated wound closure; these therapeutic benefits are partially attenuated by local CD206 blockade. Collectively, these findings demonstrate that polysaccharide-engineered mitochondria can reprogram diabetic wound macrophages via targeted mitochondrial transplantation, offering a promising immunometabolic strategy for chronic wound therapy.

Keywords: Diabetic wound healing; Engineered mitochondria; Immunometabolism; Macrophage polarization; Mitochondrial transplantation

DOI: https://doi.org/10.1016/j.bioactmat.2026.04.009

Sheng Li Xue Bao. 2026 Apr 25. 78(2): 295-305

[Mechanism of mitochondrial transcellular transfer in cerebral ischemia-reperfusion injury].

Rui-Shu An, Wen-Xiu Qin, Jian Yang, Jun-Feng Xu.

Ischemic stroke (IS) is an acute cerebrovascular disease in which blood circulation to brain tissue and neurological function are impaired due to obstruction of cerebral blood vessels, and it is one of the most common causes of death worldwide. Therapies such as intravenous thrombolysis and endovascular thrombectomy can open occluded cerebral vessels and restore blood flow through reperfusion, but ischemia/reperfusion (I/R) may trigger pathological processes such as oxidative stress, electrolyte disorders, and inflammatory responses, leading to secondary tissue damage such as cerebral edema and intracranial hemorrhage. Therefore, it is crucial to mitigate cerebral ischemia-reperfusion injury (CIRI). Mitochondria, as organelles, usually exist inside cells. However, under the stimulation of CIRI, mitochondria and their components can affect brain tissue cells by transcellular transfer through tunneling nanotubes (TNTs), gap junctions (GJs), and releasing and capturing of extracellular vesicles (EVs), etc. The mitochondrial transcellular transfer therapy for CIRI can reduce oxidative stress damage, improve neuronal energy metabolism, regulate neuroinflammation, and promote neural repair and regeneration. Mitochondrial transcellular transfer is regarded as a promising therapeutic approach for the treatment of CIRI, and in-depth investigation of the mechanism of mitochondrial transcellular transfer is expected to open up a new clinical pathway for the treatment of CIRI. This paper explores the molecular mechanism of mitochondrial transcellular transfer and its effects in the treatment of CIRI, which is expected to broaden clinical therapeutic approaches and provide a new direction for the treatment of CIRI.

DOI: https://doi.org/10.13294/j.aps.2026.0030

Nat Commun. 2026 Apr 22.

Transplantation of active mitochondria condensed in liquid-liquid phase-separated hydrogels ameliorates myocardial ischemia-reperfusion injury.

Jiacong Ai, Yingxian Xiao, Qishan Li, Yafang Xiao, Weirun Li, Junyao Deng, Weichao Ding, Rui Zhang, Shushan Mo, Yan Zeng, Xuelin Fan, Xueyi Wang, Zhenhua Li.

Mitochondrial dysfunction is a major contributor to myocardial ischemia-reperfusion injury, and limits cardiac recovery after blood flow is restored. Although mitochondria transplantation may help restore cellular energy metabolism, its therapeutic benefit is reduced by extracellular calcium-induced mitochondrial damage. Here we show that a thermosensitive phase-separated hydrogel made of gelatin and PEG can condense, protect and deliver freshly isolated mitochondria. Compared with conventional single-phase hydrogels, this system remains injectable at physiological temperature and enables rapid mitochondria release after transplantation. Furthermore, the phase-separated structure improves mitochondrial packing and preserves activity through spatial confinement and calcium chelation by gelatin. In vitro, condensed mitochondria show improved membrane potential and ATP production. In vivo, transplanted mitochondria are efficiently internalized by cardiomyocytes, improving cardiac function and reducing tissue injury after myocardial ischemia-reperfusion. These findings identify phase-separated hydrogels as a promising platform for mitochondria transplantation.

DOI: https://doi.org/10.1038/s41467-026-71765-6