Dry Eye Disease (DED) is a highly characterised multifactorial disease resulting in the loss of tear film homeostasis and associated with a major impact on patient quality of life. DED affects up to half of the global population, with modern lifestyle factors playing a critical role in disease development, particularly excessive use of digital devices. The ultimate treatment goal is restoration of tear film homeostasis and breaking the ‘vicious circle’ of DED. Today, the use of tear substitutes represents the main option for the treatment of DED. These topical formulations aim to provide lubrication, reduce osmolarity, and improve tear clearance. However, they do not interact with the ocular surface epithelium nor modulate ocular inflammation, and do not fully restore natural tear function. T-LysYal is the first supramolecular ocular surface modulator for DED. Studies demonstrate that T-LysYal promotes tissue repair, improves tear breakup time, restores corneal epithelial cell damage, and modulates inflammation processes, significantly reducing the severity of DED symptoms in patients. In addition, T-LysYal provides stability that prolongs activity and favours cell adhesion. Through its 3D nanotube structure, movement of water in the eye is retained and improved, enhancing ocular hydrodynamics. This narrative review introduces T-LysYal for DED whilst highlighting both its in vitro activity and clinical profile against hyaluronic acid, a mainstay of disease management.