Polymer micelles that are self-assembled from biocompatible amphiphilic polymers in water have emerged as one of the most promising nanocarrier systems for various hydrophobic drugs. These systems offer several advantages, such as significantly enhancing drug water solubility, decreasing side effects, and improving drug delivery to tumor tissues via the enhanced permeability and retention (EPR) effect. Recent advances in polymer micelles for drug delivery have led to systems showing “triggered” release on demand which allows restricting drug release at the targeted location by an external stimulus. Among external stimulations, light, especially when two-photon activation is used, is attractive as it can be remotely applied with a high temporal and spatial precision. In two-photon excitation, near-infrared (NIR) - infrared (IR) stimuli (700–1300 nm) are within the range of the transparency window of tissues in which the absorption and scattering of photons by tissues are low and enable deeper penetration with less photodamage to tissue in comparison to UV or visible light excitation. Although several methods have been developed for the synthesis of photoresponsive polymer micelles, most of these carrier systems have been designed from synthetic polymer backbones and were not explored in studies on whole animals. Therefore, substantial efforts in the development of light sensitive biocompatible and biodegradable polymer assemblies for future clinical applications are needed. The aim of this project is to engineer and to study a new class of NIR-light sensitive biocompatible polymer carrier systems consisting of hyaluronic acid (HA)-based nanogels that exhibit photoinduced swelling and degradation properties for remote-controlled drug release. Thermosensitive copolymer chains possessing NIR two-photon cleavable units (coumarin ester derivative) and crosslinker precursors (pyridyl disulfide (PDS) moieties or 2-ureido-4-pyrimidone (UPy) units), will be introduced on the HA backbone to produce HA derivatives that can self-assemble into multi-stimuli responsive nanogels (also considered as micelles) above the lower critical solution temperature (LCST) of the copolymer. The reversible crosslinking bonds formed from the PDS or Upy groups (disulfide bonds or quadruple H-bonds, respectively) will ensure stability of nanogels before reaching the target site in which they will be dissociated. Here, the nanogels will undergo a rapid swelling induced by the photolysis of the coumarin ester, resulting in the burst release of the drug payload. In these systems, the coumarin derivatives, having large two-photon absorption cross-sections, act as photoremovable protecting groups inducing a shift in the LCST of the copolymer due to the conversion of coumarin esters into carboxylate groups upon light irradiation. The amount of coumarin moieties in the copolymer chains will be thus adjusted in such a way that the LCST will change from a temperature below the body temperature (~ 25 °C) to a temperature higher than 37 °C (~ 45 °C), allowing for triggered drug release at body temperature. After releasing their cargo, the nanogels will disintegrate completely inside the cells, because the disulfide bonds have the propensity to be degraded in the intracellular redox environment and H-bonds between Upy units are destabilized in a highly hydrophilic environment. The originality of this approach lies in the synergistic combination of thermosensitivity and NIR-light sensitivity which will induce an important volume phase transition of the nanogels allowing efficient drug release. To obtain functional HA nanogels for photocontrolled delivery applications, we will conduct fundamental studies of their light responsiveness and release processes, and assess their performance in vivo on a mouse brain tumor model.