Abstract

Targeted protein degradation (TPD) has transformed strategies for modulating protein function in both basic biology and therapeutic development. However, current strategies often lack the spatial and temporal precision required for in vivo applications. Herein, we report supramolecular targeting chimeras (SupTACs), a modular and programmable platform that enables tissue-specific and temporally controlled protein degradation in vivo . SupTACs self-assemble into supramolecular nanoparticles (SNPs) that co-localize target-binding ligands and E3 ligase recruiters, thereby facilitating proteasomal degradation through multivalent supramolecular proximity. This strategy achieves robust and tissue-specific degradation, including liver and lung specificity, in multiple species up to non-human primates. As a proof of concept, lung-specific degradation of acyl-coenzyme A (CoA) synthetase long-chain family member 4 (ACSL4) using SupTACs effectively mitigates ferroptosis and pulmonary inflammation in a murine model of acute lung injury. By integrating modularity, tissue specificity, and temporal regulation, SupTACs establish a versatile platform for precise control of protein degradation for interrogating dynamic signaling networks and developing targeted therapeutics.