Topological Quantum Biomaterials Enable Pyroptosis‐Senescence Coupling for Enhanced Colorectal Cancer Therapy

Abstract

ABSTRACT Inducing pyroptosis in tumor cells has emerged as a promising anticancer strategy. However, under sublethal oxidative stress, a considerable fraction of cancer cells evades pyroptosis and undergoes therapy‐induced senescence, which ultimately drives chronic inflammation and facilitates tumor relapse. Here, we report an ultrasound‐responsive sequential therapeutic strategy that orchestrates the pyroptosis‐senescence axis for improved colorectal cancer therapy. This sequential therapeutic strategy integrates two functional modules, including morphologically engineered Pd3Sn topological quantum biomaterials and senolytic agent piperlongumine. Upon ultrasound irradiation, the tailored Pd3Sn nanostructures generate reactive oxygen species, which subsequently trigger zDHHC5‐mediated S‐acylation of gasdermin D, thereby initiating pyroptosis in colorectal cancer cells. Benefiting from its facet dependent near Fermi level electronic states and favorable peroxide activation kinetics, Pd3Sn achieves substantially improved sonocatalytic performance, allowing for the controlled production of radicals and the accurate triggering of the pyroptosis cascade. Intriguingly, the senescence‐associated secretory phenotype factors released from pyroptotic cells drive the surviving cancer cells into a senescent state. These senescent cells are then selectively eliminated by piperlongumine, effectively abrogating their senescence‐associated pro‐tumorigenic effects. In subcutaneous and liver metastasis models, this nanoplatform significantly suppresses tumor progression, achieving an 83.4% tumor volume inhibition rate and minimal liver metastatic burden. This work opens the application of quantum biomaterials in biomedicine and establishes a new therapeutic paradigm for disease treatment.