A Nanoinhibitor Targeting cGAS‐STING Pathway to Reverse the Homeostatic Imbalance of Inflammation in Psoriasis

Abstract

Psoriasis is a chronic skin inflammation characterized by dysregulated crosstalk between immune cells and keratinocytes. Here we show that the cyclic GMP‐AMP synthase (cGAS)‐stimulator of interferon genes (STING) pathway is a key regulator of psoriatic inflammation in a mouse model. Platinum‐doped positively charged carbon dots (Pt‐CDs) were designed to inhibit the cGAS‐STING pathway. By inhibiting the cGAS‐STING pathway with Pt‐CDs, the secretion of proinflammatory cytokines in macrophages was reduced, and the proinflammatory cytokines‐induced breakdown of immunological tolerance and overexpression of chemokines in keratinocytes was restored, which reversed the homeostatic imbalance through breaking these cytokines‐mediated intercellular positive feedback loop. Topical Pt‐CDs treatment exhibited therapeutic effects in imiquimod‐induced psoriasis mice without noticeable toxicity. The reversal of elevated expression of STING, phosphorylated STING, and downstream genes within psoriatic lesions indicates that Pt‐CDs effectively inhibit the cGAS‐STING pathway. This work suggests a promising strategy for psoriasis treatment by targeting the cGAS‐STING pathway with Pt‐CDs nanoinhibitor to restore skin homeostatic balance.

Macrophage Functions in Psoriasis: Lessons from Mouse Models

“…Finally, therapeutic blockage of IL-23 and IL-17 cytokines has also been suggested to affect monocyte/macrophage activity [124]. The release of pro-inflammatory cytokines by macrophages can also be prevented by targeting the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway [125]. Interestingly, macrophages may likely be therapeutically prompted to degrade pro-inflammatory cytokines.…”

“…targeting the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway [125]. Interestingly, macrophages may likely be therapeutically prompted to degrade pro-inflammatory cytokines.…”