ZIF-8 nanoparticles alleviate cytokine release syndrome

Cytokine release syndrome (CRS) is a critical condition involving an excessive immune response that can result in multiple organ dysfunction and potentially fatal outcomes. Here, we revealed that monocytes from CRS patients highly expressed multiple proinflammatory cytokines in single-cell RNA sequencing data. ZIF-8, a widely employed nanodrug carrier, effectively inhibits the release of diverse pro-inflammatory cytokines and suppresses NLRP3, AIM2, and NLRC4 inflammasome activation. Mechanistic studies using ATAC-seq showed that ZIF-8 inhibited the lipopolysaccharide (LPS)-induced inflammation by preventing nuclear entry of pNF-κB and IRF2. Additionally, ZIF-8 inhibited the activation of NLRP3, NLRC4, and AIM2 inflammasomes by reducing ASC specks formation. In two mouse models of CRS induced by anti-CD3 antibody therapy and LPS, ZIF-8 extends the survival of CRS mice by reducing pro-inflammatory cytokine levels. This study highlights the potential of ZIF-8 in modulating inflammation for therapeutic purposes. Additionally, it also emphasizes the consideration of ZIF-8’s immunomodulatory properties when utilizing it as a carrier in the formulation of nanomedicine. • scRNA-seq reveals monocytes as key drivers of cytokine storms in COVID-19 and HIV-induced CRS. • ZIF-8 suppresses pro-inflammatory cytokine release and inhibits multi-inflammasome activation. • ZIF-8 treatment prolongs survival and reduces inflammation in CRS models with good biocompatibility. • ATAC-seq shows ZIF-8 prevents nuclear entry of pNF-κB and IRF2 to inhibit inflammation.