Biomimetic Delivery of Cisplatin for Efficient Immunotherapy of Gasdermin E‐Positive Hepatocellular Carcinoma via a Pt Concentration‐Dependent Minimalist Pyroptosis Strategy

Abstract Compared to the classical Gasdermin D (GSDMD)‐mediated pyroptosis that has been extensively explored for cancer immunotherapy, the direct induction of Gasdermin E (GSDME) pyroptosis has been rarely reported, likely due to the well‐recognized reduced GSDME levels in solid tumors. This study reports the use of a milestone chemotherapeutic drug, cisplatin (CDDP), for effectively inducing inflammatory pyroptosis that depends on the intracellular platinum (Pt) concentration in GSDME‐positive hepatocellular carcinoma identified by bioinformatic analyses. Biomimetic delivery of CDDP via an internalizing arginine‐glycine‐aspartic acid (iRGD)‐functionalized plasma exosome (iRGD‐Pla‐Exo) guarantees an effective tumor intracellular Pt concentration above the threshold for inducing prompt and potent pyroptosis with significantly compromised systematic side effects. The CDDP‐activated antitumor immunity is disclosed to be via the cGAS‐STING pathway activation, including N‐terminal pore‐forming GSDME fragment (GSDME‐NT) production, subsequent perforation on the mitochondrial membrane, and final mitochondrial DNA (mtDNA) release. This nanoplatform, CDDP/1‐bromoacetyl‐3,3‐dinitroazetidine (RRx‐001) @iRGD‐Pla‐Exo nanoparticles (CRRPE NPs) leads to almost complete tumor eradication in a Hepa1‐6‐luc orthotopic liver cancer model by activating macrophages, and can be combined with the commercially available programmed death ligand 1 (PD‐L1) antibody immunomodulator to maintain T cells’ effector function for a prolonged survival lifetime. Overall, this study provides a conceptual advance in revealing the role of chemotherapy in mediating tumor cell pyroptosis and immune cell activation.