Cellular stress induced by the abnormal accumulation of improperly folded proteins in the endoplasmic reticulum (ER) is emerging as a major actor in disease development and an appealing actionable target. ER stress levels are under constant surveillance by the unfolded protein response (UPR), a major adaptive mechanism that lies at the core of cellular homeostasis and is responsible for cellular life-or-death decisions. The Inositol-requiring enzyme 1 (IRE1), the most conserved UPR transducer, is an ER-resident transmembrane protein with a cytosolic dual kinase/RNase activity controlling pro-survival or pro-death signals. Yet, despite >20 years of investigations, the precise molecular mechanisms by which IRE1 is activated and exerts its catalytic and scaffolding functions still remain unclear and a subject of debate. Major discoveries over the past year did not completely solve the mechanisms underlying IRE1 signaling and highlighted discrepancies in vitro and in cellular models that currently raise a plethora of new questions. The INSPIRE1 project aims to decode IRE1 molecular mechanisms of activation through a unique and novel prism at the interface of chemical biology, supramolecular chemistry and structural biology to provide a timely breakthrough in addressing this knowledge gap. At the core of the project is an integrated approach relying on three synthetic nanoplatforms, each tailored to study and address specific questions in a well-controlled environment. This unique and novel strategy promises to overcome the current limitations that hinder the full comprehension of IRE1 signaling mechanisms. The functional and structural knowledge gained will have far-reaching implications for the biological understanding of IRE1-dependent disorders and for harnessing IRE1 as a potential therapeutic target.