Prodrug de péptidos activado por ROS para la focalización covalente quimioselectiva en células cancerosas

The development of covalent drugs has renewed interest in strategies that achieve high selectivity while minimizing off-target reactivity. Herein, we report IRS1, a peptide-based prodrug comprising an integrin-targeting RGD motif, an ROS-responsive thiomorpholine unit, and a chlorambucil-derived covalent warhead for efficient cancer inhibition. Under physiological conditions, IRS1 self-assembles into nanoparticles and preferentially accumulates in uveal melanoma (UM) cells via integrin-mediated targeting. Within the tumor microenvironment, ROS-triggered oxidation of thiomorpholine induces a hydrophobic-to-hydrophilic transition, driving the nanoparticle-to-nanofibril transformation and exposing the chlorambucil moiety. This enables covalent conjugation with the thiol groups of DR4/DR5 on the cell membrane. IRS1 effectively disrupts membrane integrity, activates extrinsic apoptosis, and induces cancer cell death in vitro. In UM xenograft models, IRS1 shows potent antitumor efficacy with reduced systemic toxicity, highlighting a peptide-reconfiguration strategy for tumor-selective covalent therapeutics.