Electroporation-primed cascade nanocatalysis boosts STING-driven chemoimmunotherapy in hepatocellular carcinoma

Abstract

Nanosecond pulsed electric field (nsPEF) ablation enables non-thermal tumor destruction with favorable tissue selectivity, but its long-term efficacy is often limited by postoperative recurrence. Here, we developed an electroporation-primed, tumor microenvironment-responsive core-shell cascade nanoparticle, ZnO2-NiFc@MSCU (ZNFM), to potentiate nsPEF-mediated hepatocellular carcinoma (HCC) therapy and induce durable antitumor immunity. ZNFM contains a degradable ZnO2 core that releases Zn2+ and generates H2O2, together with an acid-responsive NiFc shell that catalyzes H2O2 into cytotoxic reactive oxygen species, thereby enhancing local tumor eradication. Meanwhile, the incorporated prodrug MSCU, generated by conjugating the STING agonist MSA-2 with curcumin, undergoes esterase-triggered hydrolysis in tumor cells to co-release both agents. Mechanistically, Zn2+ potentiates STING activation, whereas curcumin promotes immunogenic cell death and alleviates immunosuppression by inhibiting the IDO-kynurenine axis. Importantly, nsPEF pretreatment serves as a delivery primer that markedly enhances intratumoral penetration and cellular uptake of ZNFM, thereby strengthening local therapeutic activation and promoting systemic antitumor immunity. In HCC models, nsPEF + ZNFM induces marked tumor regression, promotes dendritic cell maturation, elicits robust cytotoxic T-cell responses, and suppresses tumor rechallenge. These findings establish an electroporation-enabled cascade nanotherapeutic platform for durable HCC chemoimmunotherapy.