Journal
ADVANCED SCIENCE
Volume 9, Issue 26, Pages -Publisher
WILEY
DOI: 10.1002/advs.202203353
Keywords
cancer immunotherapy; pH cascaded responsiveness; pyroptosis; size conversion; supramolecular prodrug
Categories
Funding
- National Natural Science Foundation of China [51703187, 82072996, 81874131, 32071375]
- Hubei Province International Science and Technology Cooperation Project [2021EHB027]
- Chongqing Talents of Exceptional Young Talents Project, China [CQYC202005029, cstc2021ycjh-bgzxm0061]
- Fundamental Research Funds for the Central Universities [2042021kf0216]
- Venture & Innovation Support Program for Chongqing Overseas Returnees [cx2021017]
- Innovation Platform for Academicians of Hainan Province [SQ2021PTZ0024]
- Chongqing Engineering Research Center for Micro-Nano Biomedical Materials and Devices
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The study developed a cascaded pH-activated supramolecular nanoprodrug (PDNP) that can effectively induce pyroptosis and enhance immune response through stepwise size shrinkage, combining with anti-PD-1 antibody to amplify tumor suppression.
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.
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