Sialic Acid‐Functionalized Pyroptosis Nanotuner for Epigenetic Regulation and Enhanced Cancer Immunotherapy

Abstract The efficacy of immune checkpoint blockade (ICB) in promoting an immune response against tumors still encounters challenges such as low response rates and off‐target effects. Pyroptosis, an immunogenic cell death (ICD) mechanism, holds the potential to overcome the limitations of ICB by activating and recruiting immune cells. However, the expression of the pyroptosis‐related protein Gasdermin‐E(GSDME) in some tumors is limited due to mRNA methylation. To overcome this obstacle, sialic acid‐functionalized liposomes coloaded with decitabine, a demethylation drug, and triclabendazole, a pyroptosis‐inducing drug are developed. This nanosystem primarily accumulates at tumor sites via sialic acid and the Siglec receptor, elevating liposome accumulation in tumors up to 3.84‐fold at 24 h and leading to the upregulation of pyroptosis‐related proteins and caspase‐3/GSDME‐dependent pyroptosis. Consequently, it facilitates the infiltration of CD8 + T cells into the tumor microenvironment and enhances the efficacy of ICB therapy. The tumor inhibition rate of the treatment group is 89.1% at 21 days. This study highlights the potential of sialic acid‐functionalized pyroptosis nanotuners as a promising approach for improving the efficacy of ICB therapy in tumors with low GSDME expression through epigenetic alteration and ICD.