Nanoparticle-Driven Controllable Mitochondrial Regulation through Lysosome–Mitochondria Interactome

Precise subcellular manipulation remains challenging in quantitative biological studies. After target modification and hierarchical assembly, nanoparticles can be functionalized for intracellular investigation. However, it remains unclear whether nanoparticles themselves can progressively manipulate subcellular processes, especially organellar networks. Mitochondria act as the energetic supply, whose fission dynamics are often modulated by molecular reagents. Here, using different-sized gold nanoparticles (AuNPs) as a model, we demonstrated the nanoparticle-driven controllable regulation on mitochondria. Compared with molecular reagents, AuNPs could induce size-dependent mitochondrial fission without detectable cell injury, and this process was reversible along with intracellular AuNPs’ clearance. Mechanistically, it was attributed to the AuNPs-induced enhanced organelle interactome between lysosomes and mitochondria. Lysosomal accumulation of AuNPs induced lysosomal swelling and lysosomal motility alterations, promoting mitochondrial fission through the increased “kiss” events during the “kiss-and-run” moving of the lysosome–mitochondria interactome. This study highlights the fundamental understanding to fully explore the intrinsic capability of nanoparticles by engineering their basic properties. Also, it provides practical guidance to investigate the delicate nanolevel regulation on biological processes.