Abstract

Pyroptosis is a highly immunogenic form of programmed cell death with great potential for cancer immunotherapy. However, achieving tumor-selective and intrinsically controllable induction of pyroptosis remains challenging. Here, we report a nanoparticle-based mitochondrial disruptor, termed nanoMd/PA, which acts as an intrinsic pyroptosis inducer by directly destabilizing mitochondrial membranes in tumor cells. Inspired by the membranolytic activity of antimicrobial peptides, nanoMd/PA is engineered with a guanidinium-rich shell that selectively accumulates in tumor mitochondria and disrupts membrane integrity through a pore-forming mechanism, thereby initiating gasdermin-mediated pyroptosis. The nanoparticle is further shielded with a pH-responsive polymer layer that remains inert during circulation but activates its mitochondrial-lytic function specifically within the acidic tumor microenvironment. In an orthotopic colorectal cancer model, nanoMd/PA treatment triggers robust pyroptosis, resulting in significant tumor suppression, extended survival, and potent inhibition of metastatic spread, all without detectable systemic toxicity. This work establishes a carrier-independent, nanomaterial-driven approach to induce pyroptosis through direct mitochondrial membrane disruption, offering a new paradigm for activating antitumor immunity with synthetic, intrinsically immunomodulatory nanoparticles.