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

This study develops cisplatin and 1-bromoacetyl-3,3-dinitroazetidine (RRx-001) co-loaded internalizing arginine-glycine-aspartic acid (iRGD)-engineered plasma exosomes (CRRPE NPs) to trigger GSDME-dependent pyroptosis in Gasdermin E (GSDME)-positive hepatocellular carcinoma (HCC). CRRPE NPs induce mitochondrial membrane perforation by elevating intracellular platinum levels, thereby generating the GSDME-NT fragment, releasing mitochondrial DNA (mtDNA), and activating the cGAS-STING pathway to enhance antitumor immunity.

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.