红细胞膜包裹线粒体移植提升递送效率并在多种疾病模型中改善表型

In a recent study published in Cell, Du and colleagues developed an erythrocyte membrane-based mitochondrial encapsulation platform that enables efficient transfer of functional mitochondria across cells and tissues, thereby overcoming a major delivery bottleneck in conventional mitochondrial transplantation.¹ Encapsulated mitochondria restored mitochondrial DNA (mtDNA) content and bioenergetic function, reduced pathogenic heteroplasmy in patient-derived mitochondrial disease models, and improved pathological phenotypes in mouse models of Leigh syndrome, mtDNA depletion syndrome, and Parkinson’s disease, highlighting the translational potential of engineered mitochondrial transplantation for organelle therapeutics.

Mitochondria occupy a unique position among cellular organelles because they possess their own genome while simultaneously depending on extensive coordination with the nuclear genome. Consequently, mitochondrial dysfunction can arise from mutations in either mitochondrial or nuclear DNA and contributes to a broad spectrum of diseases ranging from primary mitochondrial syndromes to common age-associated disorders. Beyond rare genetic diseases, impaired mitochondrial function is increasingly recognized as a hallmark of neurodegeneration, metabolic dysfunction, cardiovascular injury, and aging-associated tissue decline.²

Despite considerable advances in gene replacement strategies and mitochondrial genome engineering, therapeutic correction of mitochondrial dysfunction remains challenging. Efficient delivery, incomplete heteroplasmy correction, and long-term safety continue to limit the clinical applicability of current approaches.³ Mitochondrial transplantation has therefore emerged as an attractive alternative strategy because it bypasses the need to correct individual mutations and instead directly restores organelle function. However, free mitochondria are susceptible to extracellular damage, display limited uptake efficiency, and frequently undergo lysosomal degradation following internalization, reducing their therapeutic potential.⁴

To overcome these limitations, Du et al. engineered mitochondrial capsules by packaging isolated donor mitochondria within erythrocyte-derived plasma membrane vesicles, thereby establishing an organelle delivery platform that overcomes the major bottlenecks associated with conventional mitochondrial transplantation and enables functional restoration across diverse disease models (Fig. 1). The design is particularly attractive because erythrocytes naturally lack nuclei and intracellular organelles, providing a biologically clean and clinically compatible membrane source. The resulting mitochondrial capsules preserved mitochondrial membrane potential and ATP-producing activity while markedly enhancing intracellular delivery efficiency. Live-cell imaging demonstrated rapid uptake of donor mitochondria, followed by mitochondrial tubulation and stable intracellular persistence. Notably, mitochondrial transfer efficiency approached 80% of recipient cells, substantially exceeding that observed with conventional free mitochondrial transplantation.¹

The enhanced delivery efficiency translated into robust functional recovery across multiple disease models. In ρ0 cells, mitochondrial capsule transplantation restored mtDNA abundance, rescued mitochondrial ultrastructure, normalized membrane potential, and recovered oxidative phosphorylation. Similar benefits were observed in patient-derived fibroblasts carrying large-scale mtDNA deletions or the pathogenic m.3243 A>G mutation, where treatment reduced mutant heteroplasmy and restored mitochondrial protein synthesis. These findings suggest that mitochondrial transplantation may shift mitochondrial genetic composition below pathogenic thresholds, providing an alternative route to heteroplasmy correction.^1,3

Importantly, the translational relevance of this platform extended beyond cellular systems. Following systemic administration, donor mitochondria were detected in multiple organs, including the liver, heart, intestine, and brain. Delivery was also demonstrated in cynomolgus monkeys, supporting scalability beyond rodent models. In NADH: ubiquinone oxidoreductase subunit S4 (Ndufs4)-knockout (KO) mice, a widely used model of Leigh syndrome, mitochondrial capsule treatment improved survival and motor performance. Similarly, repeated administration in deoxyguanosine kinase (Dguok)-KO mice restored hepatic mtDNA abundance, improved respiratory chain activity, and alleviated liver pathology.¹

As summarized in Fig. 1, enhanced mitochondrial delivery translated into therapeutic benefits across both inherited mitochondrial disorders and neurodegenerative disease models. Perhaps the most compelling demonstration of therapeutic potential emerged in Parkinson’s disease models. In 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced Parkinsonian mice, mitochondrial capsule treatment restored tyrosine hydroxylase-positive neurons in the substantia nigra and striatum, improved motor behavior, and recovered mitochondrial respiratory chain activity. Direct stereotaxic administration into the substantia nigra further produced robust neuroprotective effects after a single injection, highlighting the possibility of targeted organelle delivery for neurological intervention.¹

Beyond its therapeutic implications, this study introduces a broader conceptual advance. Regenerative medicine has traditionally relied on cells, genes, proteins, or small molecules as therapeutic entities. In contrast, mitochondrial transplantation treats the organelle itself as the therapeutic unit. Unlike gene editing approaches, mitochondrial delivery enables immediate restoration of bioenergetic function without genomic manipulation. Unlike extracellular vesicle-mediated metabolic modulation, mitochondrial capsules deliver intact and functionally active organelles.⁴ These characteristics position mitochondrial transplantation as a distinct therapeutic modality within regenerative medicine.

Nevertheless, several important challenges remain before clinical translation can be fully realized. Achieving efficient tissue-specific targeting remains an important challenge for future clinical translation, and the biodistribution of transplanted mitochondria will require further optimization for disease-specific applications. Long-term immunological compatibility and mitochondrial–nuclear compatibility also warrant careful investigation, particularly under repeated dosing conditions. In addition, scalable Good Manufacturing Practice-compliant manufacturing, quality control, and standardization of mitochondrial preparations remain unresolved challenges. To further facilitate clinical translation, complementary large-animal models such as mini-pigs may provide valuable platforms for evaluating repeated dosing, long-term safety, biodistribution, and organ-specific therapeutic efficacy under clinically relevant physiological conditions.

Despite these limitations, Du and colleagues demonstrate that membrane-engineered mitochondrial delivery can overcome key barriers associated with conventional mitochondrial transplantation. Their study establishes encapsulated mitochondria as a distinct therapeutic modality capable of restoring organelle function without direct genomic manipulation. Future progress will require disease-specific targeting, standardized manufacturing and potency assays, long-term safety evaluation, and—as with gene and cell therapies—regulatory frameworks tailored to living organelle products, similar to those for gene and cell therapies. Addressing these challenges will be critical for this technology to establish itself as a next-generation therapeutic platform.

References

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Acknowledgements

This work was supported by the National Research Foundation of Korea (NRF) funded by the Korean government (MSIT) (RS-2021-NR057659) and the KRIBB Research Initiative Program (KQM0042611, NTM2542621, and KGM5362622).

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1. Futuristic Animal Resource and Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Cheongju, Republic of Korea

   Hae-Jun Yang, Pil-Soo Jeong & Sun-Uk Kim

2. Department of Functional Genomics, KRIBB School, Korea National University of Science and Technology (UST), Daejeon, Republic of Korea

   Sun-Uk Kim

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1. Hae-Jun Yang
2. Pil-Soo Jeong
3. Sun-Uk Kim

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H.J.Y., P.S.J. and S.U.K. designed, researched, and wrote the manuscript. All authors have read and approved the article.

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Correspondence to Hae-Jun Yang, Pil-Soo Jeong or Sun-Uk Kim.

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Yang, HJ., Jeong, PS. & Kim, SU. Encapsulated mitochondrial transplantation: Advancing organelle therapeutics. Sig Transduct Target Ther 11, 469 (2026). https://doi.org/10.1038/s41392-026-02959-z

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• Received: 07 July 2026

• Revised: 21 July 2026

• Accepted: 22 July 2026

• Published: 26 October 2026

• Version of record: 26 October 2026

• DOI: https://doi.org/10.1038/s41392-026-02959-z