Open AccessStepwise Size Shrinkage Cascade‐Activated Supramolecular Prodrug Boosts Antitumor Immunity by Eliciting Pyroptosis
Author(s) -
Liang MengYun,
Zhang MengJie,
Qiu Wei,
Xiao Yao,
Ye MengJie,
Xue Peng,
Kang YueJun,
Sun ZhiJun,
Xu Zhigang
Publication year - 2022
Publication title -
advanced science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.388
H-Index - 100
ISSN - 2198-3844
DOI - 10.1002/advs.202203353
Subject(s) - pyroptosis , ethylene glycol , chemistry , immune system , adjuvant , cancer research , materials science , biophysics , apoptosis , biochemistry , immunology , programmed cell death , medicine , biology , organic chemistry
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 penetration. Following endocytosis, second‐stage 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)‐mediated pyroptosis to enhance the immunological response. In combination with anti‐PD‐1 antibody, PDNPs can amplify tumor suppression and extend the survival of mice, which suggests a powerful immune adjuvant and pave the way for high‐efficiency immune checkpoint blockade therapy.