Biomimetic nanovesicle mediated GSDME delivery reprograms the tumor immune microenvironment via pyroptosis to enhance radiotherapy.

The anti-tumor immune response induced by radiation therapy is typically hindered by intrinsic tumor radioresistance and the insufficient release of endogenous antigens. Pyroptosis, a highly immunogenic form of programmed cell death, is regarded as a key pathway for enhancing the immunological effects of radiotherapy. However, Gasdermin E (GSDME) is under-expressed in most tumor cells, which significantly diminishes the activation of the pyroptosis pathway and confers tumor tolerance to pyroptosis-based therapies. To address this issue, this study designed a biomimetic nanovesicle (pGSDME@TLNV) by fusing B16F10 tumor cell membranes with cationic lipid transfection reagent (Lipofectamine 3000), which can specifically target tumor cells and deliver a GSDME overexpression plasmid. This approach aims to enhance radiotherapy-induced pyroptosis by upregulating GSDME expression to trigger anti-tumor immune responses. The biomimetic nanovesicle exhibits notable immune evasion capabilities and homologous targeting properties, enabling efficient delivery and elevated GSDME protein expression within tumor cells. Following combined radiotherapy, pGSDME@TLNV significantly promotes tumor cell pyroptosis and releases the proinflammatory cytokines IL-18 and IL-1β, which effectively drive dendritic cell (DC) maturation. Simultaneously, tumor-associated antigens released during pyroptosis synergize with the antigens carried by the nanovesicle itself, further enhancing the antigen-presenting capacity of dendritic cells. This cascade of immune activation ultimately engages antigen-specific T cells, triggering robust anti-tumor immune responses that markedly suppress tumor growth. Collectively, as a nanomaterial system that integrates biomimetic delivery and immune regulation functions, pGSDME@TLNV significantly enhances anti-tumor immune responses through multiple mechanisms, including synergizing with radiotherapy, inducing pyroptosis and activating DCs and T cells. This strategy offers a novel approach for radioimmunotherapy in GSDME-low tumors and helps inform the design of next-generation biomimetic delivery platforms.