Inhibiting stimulator of interferon genes (STING) is critical for treating rheumatoid arthritis (RA), yet achieving precise suppression with high tissue specificity across protein variants remains challenging. Here, we engineer a multilevel, intelligent STING degrader—charge-reversal proteolysis-targeting chimeras (CreTACs)—that efficiently delivers to RA sites and degrades STING variants in humans, mice, and rats. Unlike traditional degraders with systemic toxicity, this charge reversal platform leverages pH-programmed charge inversion: Electroneutrality in circulation (pH 7.4) minimizes toxicity, while acidic-triggered protonation enables a 7.5-fold increase in arthritic joint accumulation (tissue level), pH-gated cellular internalization (80% uptake at pH 6.5 vs. 50% at pH 7.4; cellular level), and enhanced cytoplasmic STING (proton channel) affinity via charge interactions (protein level). In collagen-induced arthritis models, CreTACs outperformed methotrexate by suppressing synovitis and bone erosion without hematological toxicity. This multilevel charge reversal strategy establishes a blueprint for next-generation proteolysis drug-delivery systems or biomaterials, offering transformative potential for healthcare.
He et al. (Thu,) studied this question.