ESCRT‐Mimetic Nanodegrader Targets STING for Anti‐Inflammatory Therapy

ABSTRACT Excessive STING activation underlies the pathogenesis of diverse inflammatory diseases, yet conventional inhibitors often fail to restore its physiological degradation. To address this, we designed a biomimetic STING‐directed autophagy‐targeting chimera (STING‐ATTEC) that recapitulates the endogenous ESCRT‐mediated degradation pathway, with computational modeling providing preliminary guidance for molecular optimization. The optimized STING‐ATTEC was encapsulated within folate‐modified cationic lipid nanoparticles (FA‐LNP ⁺ ), formulated with DOTAP to enhance autophagic activity and promote lysosomal trafficking. This combined strategy synergistically amplified STING degradation, leading to potent suppression of inflammatory signaling, mitigation of tissue damage, and promotion of tissue regeneration across multiple disease models. These findings illustrate a cooperative material‐based strategy that enhances autophagy and enables targeted protein degradation, positioning lysosome‐targeting degraders as a promising translational modality for immunomodulatory therapy.