ESCRT-Mimetic Nanodegrader Targets STING for Anti-Inflammatory Therapy.

Area of Science:

• Immunology and Molecular Biology
• Biomaterials and Nanotechnology

Background:

• Excessive STING (stimulator of interferon genes) activation drives inflammatory diseases.
• Current STING inhibitors often fail to induce physiological degradation of STING.
• Need for novel therapeutic strategies to target STING degradation.

Purpose of the Study:

• To design and evaluate a biomimetic STING-directed autophagy-targeting chimera (STING-ATTEC).
• To enhance STING degradation and suppress inflammatory signaling.
• To explore a material-based strategy for targeted protein degradation and immunomodulation.

Main Methods:

• Design of STING-ATTEC to mimic endogenous ESCRT-mediated degradation pathways.
• Computational modeling for molecular optimization of STING-ATTEC.
• Encapsulation of STING-ATTEC in folate-modified cationic lipid nanoparticles (FA-LNP+).
• Formulation with DOTAP to enhance autophagy and lysosomal trafficking.

Main Results:

• The combined strategy synergistically amplified STING degradation.
• Potent suppression of inflammatory signaling was observed.
• Mitigation of tissue damage and promotion of tissue regeneration in multiple disease models.

Conclusions:

• STING-ATTEC delivered via FA-LNP+ effectively targets STING for degradation.
• This approach demonstrates a promising material-based strategy to enhance autophagy.
• Lysosome-targeting degraders represent a viable translational modality for immunomodulatory therapy.