An epigenetic regulator synergizes with alphavirus-mediated gene therapy via biomimetic delivery for enhanced cancer therapy.

Gene therapy is promising for treating genetic disorders, but faces challenges in treating cancer due to the intricate genetic and immunosuppressive landscape of this disease. Here, we describe a technology combining alphavirus-based gene therapy with an epigenetic regulator via pyroptosis and immune checkpoints to address these challenges. A filamentous actin-mimicking liposomal delivery system, with high fusion efficiency, was developed that encapsulates the Semliki Forest virus (pSFV) DNA vector to deliver p53 and PDL1 scFv DNA, bypassing traditional endocytic barriers to deliver genes with high efficiency via membrane fusion. To enhance this combined therapy, the DNA methyltransferase inhibitor decitabine (DAC) was used to increase Gasdermin E (GSDME) expression, converting apoptosis to pyroptosis. This approach kills apoptosis-resistant tumor cells, and also promotes T cell infiltration and activation, facilitating an anti-PDL1 therapy and the systemic antitumor immune response. This multifaceted therapeutic strategy combines gene therapy with epigenetic regulation to significantly improve immune checkpoint therapy (ICT) effectiveness, offering a robust potential as a transformative cancer treatment.