GSDMD-dependent pyroptotic induction by a multivalent CXCR4-targeted nanotoxin blocks colorectal cancer metastases

Rita Sala, Elisa Rioja-Blanco, Naroa Serna, Laura Sánchez-García, Patricia Álamo, Lorena Alba-Castellón, Isolda Casanova, Antonio López-Pousa, Ugutz Unzueta, María Virtudes Céspedes, Esther Vázquez*, Antonio Villaverde, Ramon Mangues*

*Corresponding author for this work

Research output: Contribution to journalArticleResearchpeer-review

13 Citations (Scopus)


Colorectal cancer (CRC) remains the third cause of cancer-related mortality in Western countries, metastases are the main cause of death. CRC treatment remains limited by systemic toxicity and chemotherapy resistance. Therefore, nanoparticle-mediated delivery of cytotoxic agents selectively to cancer cells represents an efficient strategy to increase the therapeutic index and overcome drug resistance. We have developed the T22-PE24-H6 therapeutic protein-only nanoparticle that incorporates the exotoxin A from Pseudomonas aeruginosa to selectively target CRC cells because of its multivalent ligand display that triggers a high selectivity interaction with the CXCR4 receptor overexpressed on the surface of CRC stem cells. We here observed a CXCR4-dependent cytotoxic effect for T22-PE24-H6, which was not mediated by apoptosis, but instead capable of inducing a time-dependent and sequential activation of pyroptotic markers in CRC cells in vitro. Next, we demonstrated that repeated doses of T22-PE24-H6 inhibit tumor growth in a subcutaneous CXCR4+ CRC model, also through pyroptotic activation. Most importantly, this nanoparticle also blocked the development of lymphatic and hematogenous metastases, in a highly aggressive CXCR4+ SW1417 orthotopic CRC model, in the absence of systemic toxicity. This targeted drug delivery approach supports for the first time the clinical relevance of inducing GSDMD-dependent pyroptosis, a cell death mechanism alternative to apoptosis, in CRC models, leading to the selective elimination of CXCR4+ cancer stem cells, which are associated with resistance, metastases and anti-apoptotic upregulation.

Original languageEnglish
Pages (from-to)1384-1397
Number of pages14
JournalDrug Delivery
Issue number1
Publication statusPublished - 2022


  • colorectal cancer
  • CXCR4
  • Metastasis
  • PE24 exotoxin
  • pyroptosis
  • targeted nanoparticle


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