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However, the actual efficacy of the present pyroptosis inducers can be weakened by successive biological barriers. Here, a cascaded pH\u2010activated supramolecular nanoprodrug (PDNP) with a stepwise size shrinkage property is developed as a pyroptosis inducer to boost antitumor immune response. PDNPs comprise multiple poly(ethylene glycol) (PEG) and doxorubicin (DOX) drug\u2013polymer hybrid repeating blocks conjugated by ultra\u2010pH\u2010sensitive benzoic imine (bzi) and hydrazone (hyd) bonds. The PEG units endow its \u201cstealth\u201d property and ensure sufficient tumor accumulation. A sharp switch in particle size and detachment of PEG shielding can be triggered by the acidic extracellular pH to achieve deep intratumor penetration. Following endocytosis, second\u2010stage size switching can be initiated by more acidic endolysosomes, and PDNPs disassociate into ultrasmall cargo to ensure accurate intracellular delivery. The cascaded pH activation of PDNPs can effectively elicit gasdermin E (GSDME)\u2010mediated pyroptosis to enhance the immunological response. In combination with anti\u2010PD\u20101 antibody, PDNPs can amplify tumor suppression and extend the survival of mice, which suggests a powerful immune adjuvant and pave the way for high\u2010efficiency immune checkpoint blockade therapy.<\/jats:p>","DOI":"10.1002\/advs.202203353","type":"journal-article","created":{"date-parts":[[2022,7,23]],"date-time":"2022-07-23T01:20:47Z","timestamp":1658539247000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":68,"title":["Stepwise Size Shrinkage Cascade\u2010Activated Supramolecular Prodrug Boosts Antitumor Immunity by Eliciting Pyroptosis"],"prefix":"10.1002","volume":"9","author":[{"given":"Meng\u2010Yun","family":"Liang","sequence":"first","affiliation":[{"name":"State Key Laboratory of Silkworm Genome Biology School of Materials and Energy and Chongqing Key Laboratory of Soft\u2010Matter Material Chemistry and Function Manufacturing Southwest University  Chongqing 400715 P. R. 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