Mitochondria‐Targeted Chemodynamic Nanoagent Synergizes With Transcriptional Modulation for Enhanced Pyroptosis Immunotherapy

ABSTRACT Pyroptosis represents an important pathway to initiate immunogenic cell death (ICD) mediated by N‐terminal fragment of gasdermin E (GSDME‐N). Although chemodynamic therapy (CDT) has the potential to elicit pyroptosis, epigenetic silencing of gasdermin E (GSDME) in tumor cells commonly shifts cell fate toward immunologically silent apoptosis. Herein, we develop a mitochondria‐targeted CDT agent (Mito‐CA/TA NPs) that incorporates tetrachloro‐p‐benzoquinone (chloranil, CA) with transcriptional regulator triamcinolone acetonide (TA) for enhanced pyroptosis immunotherapy. The encapsulated CA facilitates chemodynamic conversion of intramitochondrial hydrogen peroxide (H 2 O 2 ) into hydroxyl radicals (•OH) under physiological pH, surmounting the acidic constraint of classical Fenton chemistry‐based CDT. Simultaneously, H 2 O 2 ‐induced hydrophilic transformation of CA ensures TA release to rescue GSDME downregulation in cancer cells, reversing epigenetic silencing of GSDME. Intramitochondrial •OH generation by Mito‐CA/TA NPs in situ disrupts mitochondrial integrity, leading to cytochrome c release and subsequent caspase‐3 activation, which causes the proteolytic cleavage of transcriptionally upregulated GSDME into GSDME‐N. Additionally, integrating •OH‐responsive chemiluminescent functionality into Mito‐CA/TA NPs enables real‐time monitoring of •OH formation and chemodynamic immunotherapeutic processes. The coordinated action of GSDME restoration and in situ mitochondrial •OH generation potently triggers pyroptosis to stimulate systemic antitumor immune responses, offering a universal strategy for improving pyroptosis‐based cancer immunotherapy.