Mitochondria as a target for nanomaterials: from molecular mechanisms of toxicity to therapeutic strategies.

Mitochondria, functioning as central integrators of metabolic signals, redox homeostasis, and programmed cell death, represent a critical intracellular compartment that dictates the biological response to engineered nanomaterials (NMs). This review provides a comprehensive analysis of the current understanding of the dualistic nature of nano-mitochondrial interactions - from the fundamental mechanisms of nanotoxicology to the principles of rational design for mitochondria-targeted therapeutic systems. The work details the hierarchical cascade of mitochondrial dysfunction development, initiated by the direct physicochemical impact of NMs on electron transport chain (ETC) complexes and potentiated by lysosome-mediated ion release (the "Trojan horse effect"). This primary damage induces a vicious cycle of reactive oxygen species (ROS) generation, leading to oxidative destruction of mitochondrial DNA (mtDNA), disruption of organelle dynamics (fusion/fission), and permeabilization of mitochondrial membranes. The loss of mitochondrial membrane potential (ΔΨm) is a terminal event converging into various modes of cell death, including intrinsic apoptosis, ferroptosis, and cuproptosis. A key tenet of this review is demonstrating the modulating role of the physicochemical characteristics of NMs (size, shape, surface chemistry, and core composition), which determine the vector and intensity of bio-nano interactions at the subcellular level. Concurrently, the paradigm shift towards harnessing these described mechanisms for therapeutic purposes is analyzed. Modern strategies for mitochondrial targeting are highlighted, particularly functionalization with lipophilic cations (e.g., triphenylphosphonium, TPP+), enabling selective accumulation of therapeutic agents driven by the high ΔΨm. Special emphasis is placed on the context-dependent pharmacology of selenium nanoparticles (SeNPs), revealing their dual nature: on one hand, they act as pro-oxidants, initiating mitochondrial apoptosis in the acidic tumor microenvironment; on the other, they realize cytoprotective potential in stem cells through miR-20b-mediated activation of selenoproteins (GPX4, TrxR), restoring bioenergetics and stimulating the intercellular transfer of functionally competent mitochondria. The deconstruction of the molecular mechanisms of nano-mitochondrial interaction creates a conceptual framework both for minimizing the toxicological risks associated with NM application and for developing next-generation precision mitochondria-targeted therapeutic platforms.