Temporal remodeling of the post–irreversible electroporation stromal–immune barrier in pancreatic cancer via dual-targeted microspheres

Irreversible electroporation (IRE) efficacy in pancreatic cancer is limited by post-ablation stromal barriers and immune suppression. To address this, we engineered temporally staggered gas-releasing short fiber–microspheres (NOHSM) that spatiotemporally coordinate NO and H 2 S delivery. NOHSM sensitizes pancreatic cancer to IRE by sequentially dismantling the robust extracellular matrix barrier and reversing post-ablation immunosuppression. Mechanistically, the outer short fibers rapidly release NO in response to the glutathione-rich tumor microenvironment. This NO reacts with IRE-induced reactive oxygen species to form peroxynitrite, which activates matrix metalloproteinases to degrade the rigid stroma. Concurrently, the inner hydrogel microspheres continuously generate H 2 S via enzymatic catalysis by tumor-overexpressed cystathionine β-synthase, which inhibits STAT3 phosphorylation to reverse the IRE-induced surge in pro-tumorigenic Th17 cell differentiation. Furthermore, NOHSM triggers a robust antitumor immune cascade, promoting dendritic cell maturation, M1 macrophage polarization, and enhanced CD8 + T cell cytotoxicity. In murine orthotopic pancreatic tumor models, local administration of NOHSM following IRE demonstrated potent primary tumor suppression and elicited a systemic abscopal effect that inhibited distant liver and lung metastases. This work establishes NOHSM as an intelligent IRE-responsive platform to overcome stromal and immune barriers in pancreatic cancer ablation therapy.