Reversing immunotherapy resistance in cold tumors by weaponizing pyroptosis with a dual-payload nanotuner.

The efficacy of immune checkpoint blockade (ICB) is often constrained by insufficient tumor antigenicity and consequent weak immune activation. Among immunogenic cell death (ICD) modalities, gasdermin-mediated pyroptosis presents a promising strategy to counteract this limitation and potentiate ICB. However, it remains challenging to engineer nanoplatforms that reliably induce pyroptosis via coordinated activation of multiple pathways. Here, we report a sialic acid-functionalized lipid nanoparticle (LNP) that co-delivers GSDME mRNA and a self-assembling small molecule (1541B) as a potent pyroptosis amplifier. Delivered GSDME mRNA bypasses epigenetic silencing and replenishes the pyroptotic substrate, while 1541B self-assembles intracellularly into nanofibers that directly activate caspase-3, cleaving GSDME to initiate non-canonical pyroptosis. Moreover, these nanofibers disrupt mitochondrial function, leading to caspase-1-mediated GSDMD cleavage, thereby amplifying pyroptotic cell death via the canonical pathway. This dual-pathway engagement enhances the release of pro-inflammatory cytokines and remodels the tumor immune microenvironment. As a result, this nano-pyroptosis inducer overcomes resistance to anti-PD-1 therapy, triggering potent systemic anti-tumor immunity and significantly inhibiting tumor growth. Overall, our findings establish a novel therapeutic paradigm for reversing ICB resistance via orchestrated pyroptosis amplification.