Guiding synthetic nanomaterials toward specific cells and subcellular organelles remains a critical challenge for targeted therapeutics. Here, we report that ATPase-functionalized nanoparticles harness enzymatic turnover to autonomously navigate extracellular and intracellular ATP gradients, accumulating near cell surfaces, experiencing enhanced uptake, and once endocytosed, localizing selectively to mitochondria in both primary human aortic endothelial cells and HeLa cells. ATP depletion or ATPase inhibition abolishes accumulation and disrupts mitochondrial targeting, confirming the requirement for active enzymatic turnover. This targeting mechanism is preserved across particle types, including lipid-based vesicles, indicating broad applicability. This work establishes enzyme-powered chemotaxis as a route to pericellular accumulation, enhanced endocytosis, and organelle-specific delivery, providing a foundation for responsive nanomedicines targeting metabolically active disease environments. The strategy shifts the paradigm from passive, receptor-based delivery to dynamic, energy-responsive targeting.
Shandilya et al. (Tue,) studied this question.