The organelle-targeting duality of nanomaterials: physicochemical property-guided therapeutic effects and toxicological outcomes.

The rapid development of nanomedicine has enabled therapeutic intervention at the subcellular scale, making organelles important targets for diseases such as cancer, neurodegenerative disorders, and metabolic syndrome. However, nanomaterial-mediated organelle targeting exhibits a context-dependent biological duality: organelles can serve as therapeutic targets for restoring normal functions or disrupting pathological processes, but they may also act as vulnerable sites for toxicological damage. This duality is governed by nanomaterial physicochemical properties, including size, morphology, surface charge, surface modification, and chemical composition, and is further influenced by protein corona formation, cell type, disease microenvironment, and immune-cell interactions. In this review, we summarize the principles of cellular internalization and subcellular trafficking, and discuss how nanomaterial properties regulate targeting efficiency and biological outcomes in lysosomes, mitochondria, the endoplasmic reticulum, and the nucleus. We also highlight inter-organelle crosstalk, immune-cell-specific responses, and the potential of less-explored organelles. Based on current evidence, we propose a trend-based semi-quantitative framework and a forward-looking safety-oriented design strategy for organelle-targeting nanomedicines. Overall, this review clarifies the mechanistic links among nanomaterial properties, biological context, organelle-level behaviors, and therapeutic-toxicological outcomes, providing a theoretical basis for the rational development of next-generation organelle-targeting nanomedicines.