Homologous targeted neutrophils-liposome system for pyroptosis-enhanced antitumor immunotherapy of triple-negative breast cancer

Triple-negative breast cancer (TNBC), characterized by negative expression of estrogen receptor, progesterone receptor, and oncogene HER-2, always exhibits resistance to targeted drugs. Immunotherapies have demonstrated promising clinical responses and significant potential for TNBC treatment. Enhancing and activating antitumoral immunity can help restrain TNBC progression. In this work, we developed and validated an irradiation-responsive, tumor-targeting, and pyroptosis-enhanced drug delivery system based on neutrophils for effective TNBC treatment. Specifically, TNBC cell membrane-derived liposomes were loaded with photothermal agent IR775 and a pyroptosis-promoting plasmid carrying GSDME coding sequence (GI-LNPs). These GI-LNPs were then anchored onto the surface of neutrophils via biotin-avidin interaction and delivered into the tumor through local injury-driven neutrophil infiltration. Compared to conventional therapeutic strategies, NE-GI-LNPs accumulated and penetrated more deeply into tumor tissues. Furthermore, IR775-triggered the generation of caspase-3 under NIR laser irradiation promoted the cleavage of expressed GSDME, converting apoptosis to pyroptosis in 4T1 cells and enhancing antitumor immunity. Overall, our study demonstrated that multifunctional GI-LNPs delivered by neutrophils could effectively inhibit tumor growth through pyroptosis-enhanced antitumor immunotherapy.