Biotechnological approaches and therapeutic potential of mitochondria transfer and transplantation

Abstract

Mitochondrial dysfunction contributes to aging and diseases like neurodegeneration and cardiovascular disorders. Mitochondria transfer and transplantation (MTT) represent promising therapeutic strategies aimed at restoring cellular function by introducing functional mitochondria into damaged cells. However, challenges like transfer efficiency, stability, and cellular integration limit clinical application. Recent biotechnological advances-such as liposomes, extracellular vesicles, and surface modifications-enhance mitochondrial protection, targeting, and biocompatibility. This Perspective highlights recent progress in MTT, its therapeutic potential, and current limitations. We also discuss the need for scalable, clinically translatable approaches and appropriate regulatory frameworks to realize the full potential of mitochondria-based nanotherapies in modern medicine.

Fig. 1. Mitochondria isolation, delivery, and transplantation mechanisms in mammalian cells.

The figure depicts the workflow and cell mechanisms involved in mitochondria isolation and transfer into mammalian cells. Left panel – Isolation and transfer of mitochondria: Mitochondria can be isolated from in vitro cultured muscle tissues or stem cells through differential centrifugation and purification. The isolated mitochondria obtained are then delivered into in vitro or in vivo mammalian recipient cells. The isolation process must preserve mitochondrial structure and bioenergetic function to support successful transplantation. Right panel – Mechanisms of mitochondria transfer/transplantation: Once introduced into the extracellular space, mitochondria can be delivered via various routes. One of the methods involves vesicle-mediated transfer, whereby mitochondria are encapsulated in extracellular vesicles that fuse with the target cell membrane and release their contents. Alternatively, free mitochondria may directly interact with surface receptors or become internalized through endocytosis-like mechanisms. Within the cell, mitochondria have two fates: they can fuse into host mitochondrial networks through mitochondrial fusion, restoring bioenergetic function, or become directed towards lysosomal breakdown if recognized as defective or foreign. Mitochondria ingestion may trigger intracellular transduction cascades by secondary messengers, further impacting recipient cell physiology. Symbols: colors in the figure represent major components: red mitochondria, yellow/orange vesicles, green fused mitochondria, and purple/blue lysosomes. Created in BioRender. Tuncay, E. (2025) https://BioRender.com/uxkej53.

Fig. 2. Strategies and challenges in mitochondria isolation and delivery for therapeutic applications.

A Isolated mitochondria from donor tissues such as skeletal muscle must preserve their functional integrity throughout the course of isolation. Isolation must be achieved rapidly and gently to prevent mitochondrial injury or loss of bioenergetics competence. Following administration into the body, exogenous mitochondria are faced with a series of rigorous challenges. These include risk of immune activation, need for stability in the extracellular environment, and ability to permeate biological barriers—like the vascular endothelium and cell membranes—to access their intracellular targets. B To address these challenges and improve delivery efficiency, various strategies have been conceived. These encompass encapsulation in natural extracellular vesicles (e.g., MVs or exosomes), which provide immune protection and target-specific delivery; engineered vesicles, e.g., synthetic nanocarriers or liposomes, which allow for surface functionalization for enhanced stability and targeting; hydrogels and hydrophilic biocompatible polymers, which can be used as scaffolds for local or long-term mitochondrial release; and surface modification techniques, e.g., coating mitochondria with ligands, antibodies, or cell-penetrating peptides, to facilitate cellular uptake and trafficking. Each delivery vehicle is designed to address principal challenges facing mitochondrial therapy, such as immunogenicity, degradation, and poor biodistribution. Color coding and icons are utilized to symbolize crucial components: red mitochondria, red-colored muscle tissue, pink/red vasculature, and purple and blue immune cells. Encapsulation strategies are symbolized by schematic vesicles and hydrogels encapsulating mitochondria, highlighting protective or targeting aspects. Created in BioRender. Nuzzo, D. (2025) https://BioRender.com/b73b997.

Fig. 3. Mitochondria delivery across the blood-brain barrier to central nervous system (CNS) cells.

This figure shows that mitochondria reach the brain; they must cross the blood-brain barrier (BBB). Furthermore, once they have reached the brain parenchyma, they must be internalized by neurons, astrocytes, oligodendrocytes, and microglia to perform their function. The entry of mitochondria (red) into the CNS space from the vasculature is shown here, with arrows indicating their potential uptake routes in neurons (brown), oligodendrocytes (purple), astrocytes (light orange), and microglia (gold). The structure of the BBB is shown in stylized purple and pink, and endothelial cells and red blood cells are shown in cross-section. The photograph highlights the clinical potential of MTT in the treatment of CNS disorders, as well as the significant challenge of crossing the BBB—a major obstacle to neurotherapeutic delivery. Created in BioRender. Nuzzo, D. (2025) https://BioRender.com/l33k213.