STING inhibitors(Shanghai Jiao Tong University)

Stimulator of interferon genes (STING) is involved in various autoimmune diseases. However, it is challenging to develop small-molecule STING inhibitors with potent activity. Herein, we designed a small-molecule STING inhibitor and STING mutant-specific degrader by binding two coupled pockets of a STING dimer. Structure optimization selected SI-24, SI-42, and SI-43 with low nanomolar activity to inhibit 2'3'-cyclic GMP-AMP (cGAMP)-induced STING activation and release of IFN-β and CXCL-10, which were far more potent than reported STING inhibitors. Moreover, the three lead compounds suppressed cGAMP-induced oligomerization of STING and phosphorylation of interferon regulatory factor 3 (IRF3) and STING. Surprisingly, SI-43 promoted mutant-specific and proteasome-independent degradation of STING^S154 and STING^M155. Subcutaneous or oral administration of SI-24, SI-42, and SI-43 reduced serum IFN-β and CXCL-10 in the cGAMP-induced autoimmune disease mouse model. Our dual-functional compounds provide a new strategy to investigate STING function through both inhibition and mutant-specific degradation in autoimmune diseases.

Imbalanced production and clearance of amyloid-β (Aβ) is a hallmark pathological feature of Alzheimer’s disease (AD). While several monoclonal antibodies targeting Aβ have shown reductions in amyloid burden, their impact on cognitive function remains controversial, with the added risk of inflammatory side effects. Dysregulated stimulator of interferon genes (STING) signaling is implicated in neurodegenerative disorders, yet the biological interaction between this pathway and Aβ, as well as their combined influence on AD progression, is poorly understood. Here, we show that while microglia play a protective role in clearing extracellular Aβ, excessive Aβ engulfment triggers the cytosolic leakage of mitochondrial DNA for cGAS–STING cascade. This creates a negative feedback loop that not only exacerbates neuroinflammation but also impairs further Aβ clearance. To address this, we present a nanomedicine approach termed “Aβ-STING Synergistic ImmunoSilencing Therapy (ASSIST)”. ASSIST comprises STING inhibitors encapsulated within a blood–brain barrier (BBB)-permeable polymeric micelle that also serves as an Aβ scavenger. Through a multivalent interaction mechanism, ASSIST efficiently destabilizes Aβ plaques and prevents monomer aggregation, subsequently promoting the engulfment of the dissociated Aβ by microglia rather than neurocytes. Furthermore, the STING signaling induced by excessive Aβ uptake is blocked, reducing inflammation and restoring microglial homeostatic functions involved in Aβ clearance. Intravenous administration of ASSIST significantly reduces Aβ burden and improves cognition in AD mice, with minimal cerebral amyloid angiopathy or microhemorrhages. We provide a proof-of-concept nanoengineering strategy to target the maladaptive immune feedback loop arising from conventional immunotherapy for AD treatment.