Mitochondrial transfer through tunneling nanotubes inspires an innovative strategy for intercellular drug delivery

The efficacy of drug delivery, particularly for solid tumors, is severely hampered by a cascade of biological barriers-including dense extracellular matrix, high interstitial fluid pressure, and inefficient vascularization-that limit therapeutic penetration and distribution. Biological materials, such as cells, extracellular vesicles and organelles, serve as biocompatibility and targeted delivery vehicles, offering significant therapeutic potential. However, most current strategies emphasize multifunctional and biomimetic delivery systems designed to traverse the extracellular stroma, often overlooking intracellular transport pathways. Here, we demonstrate that mitochondria and their hitchhiked cargos are transported via tunneling nanotubes (TNTs), contiguous cytoplasmic bridges that interconnect cells. Oxidative stress plays a pivotal role in stimulating both TNTs formation and mitochondrial transfer. By leveraging TNTs as an intracellular highway, we achieved intercellular transport and deep tissue penetration of the photosensitizer IR780, which was hitchhiked onto mitochondria (designated as IR780/Mito). The intensity of near-infrared (NIR) light governs TNTs dynamics, either promoting formation or inducing cleavage, by modulating oxidative stress levels generated upon IR780 excitation. Under mild NIR irradiation, moderate oxidative stress enhances TNTs formation and facilitates IR780/Mito transfer, enabling efficient delivery directly into tumor cells. Conversely, intense NIR irradiation triggers excessive reactive oxygen species (ROS) production, leading to TNT disruption and subsequent blockade of IR780/Mito transport. These findings present emerging opportunities for exploration into the use of TNTs transshipment channel to realize controllable intracellular transport of different types of cargos, with broad and promising applications in the diagnosis and treatment of multiple diseases in the future. STATEMENT OF SIGNIFICANCE: This work presents a new strategy for delivering drugs deep into tumors by hijacking the body's own cellular "highways"-tunneling nanotubes (TNTs). Instead of designing synthetic nanoparticles, we load drugs directly onto mitochondria, the cell's energy units, which naturally travel between cells via TNTs. Using a safe near‑infrared light, we can precisely turn this delivery route on or off by controlling the level of cellular stress: mild light promotes transport, while strong light shuts it down. This approach leverages natural cell‑to‑cell communication to overcome physical barriers in solid tumors, offering a smart, biocompatible platform for improving precision cancer therapy and treating other diseases involving intercellular signaling.