biostudies-literatureLiang MYHubei Province International Science and Technology Cooperation ProjectFundamental Research Funds for the Central UniversitiesProgram for Chongqing Overseas ReturneesChongqing Talents of Exceptional Young Talents Project, ChinaInnovation Platform for Academicians of Hainan ProvinceNational Natural Science Foundation of Chinae2203353https://www.ebi.ac.uk/biostudies/studies/S-EPMC9475545biostudies-literatureUnknown9(26)Effective pyroptosis induction is a promising approach to potentiate cancer immunotherapy. However, the actual efficacy of the present pyroptosis inducers can be weakened by successive biological barriers. Here, a cascaded pH-activated 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-polymer hybrid repeating blocks conjugated by ultra-pH-sensitive benzoic imine (bzi) and hydrazone (hyd) bonds. The PEG units endow its "stealth" 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 peAdvanced science (Weinheim, Baden-Wurttemberg, Germany)Stepwise Size Shrinkage Cascade-Activated Supramolecular Prodrug Boosts Antitumor Immunity by Eliciting Pyroptosis.PMC9475545CQYC202005029SQ2021PTZ0024818741315170318782072996cstc2021ycjh-bgzxm00612042021kf021632071375cx20210172021EHB027Sun ZJQiu WLiang MYZhang MJKang YJYe MJXue PXiao YXu ZfalseStepwise Size Shrinkage Cascade-Activated Supramolecular Prodrug Boosts Antitumor Immunity by Eliciting Pyroptosis.Effective pyroptosis induction is a promising approach to potentiate cancer immunotherapy. However, the actual efficacy of the present pyroptosis inducers can be weakened by successive biological barriers. Here, a cascaded pH-activated 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-polymer hybrid repeating blocks conjugated by ultra-pH-sensitive benzoic imine (bzi) and hydrazone (hyd) bonds. The PEG units endow its "stealth" 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 pe2022-01-01T00:00:00Z2022 Sep2025-04-04T20:19:44.072Z2025-04-04T20:19:44.072ZS-EPMC94755453586961410.1002/advs.202203353