Genetically engineered GSDME vesicle coated nanoparticle for immune activating and pyroptosis inducing synergetic therapy of fibrosarcoma

Fibrosarcoma is a kind of highly malignant sarcoma with high recurrence rate after surgery and unsatisfying efficacy of radiotherapy and chemotherapy. Increasing the concentration of gasdermin in tumor cell to induce pyroptosis is a promising strategy to treat fibrosarcoma. However, the poor cytotoxic T lymphocytes (CTL) infiltration in tumor area limits the therapeutic effect with disabled positive feedback between pyroptosis and anti-tumor immunity. Induing tumor immunogenic cell death to activate anti-tumor immune and delivering gasdermin E (GSDME) to enhance tumor pyroptosis will rebuild the positive feedback. Hence, we proposed and constructed a genetically engineered GSDME vesicle coated nanoparticle (HV-FI) to achieve effective treatment of fibrosarcoma. First, the GSDME membrane-expressing tumor cells are constructed and the GSDME-displaying vesicles are extracted. Then the HV-FI is prepared by hybridizing red blood cell membranes and encapsulating ICG-loaded mesoporous Fe₃O₄ nanoparticles. The GSDME proteins on the vesicles can effectively induce fibrosarcoma cell pyroptosis with granzyme B. After NIR irradiation, fibrosarcoma cells released DAMPs and activated dendritic cells <i>in vitro</i>. In animal experiments, fibrosarcoma cells underwent pyroptosis and CTL infiltration was boosted in tumor microenvironment. That subsequently enhanced tumor cell pyroptosis with delivered GSDME, creating a synergetic effect of tumor cell pyroptosis and anti-tumor immune activation, ultimately leading to effective tumor clearance. Meanwhile, the immunological memory is established, preventing tumor recurrence after treatment. This work proposes and validates the applicability and effectiveness of nanotherapy based on enhanced tumor pyroptosis induction and immune activation, providing a new method for the treatment of unresectable fibrosarcoma.