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Research Article

Inspired heat shock protein alleviating prodrug enforces immunogenic photodynamic therapy by eliciting pyroptosis

Junjie Zhou1,§Xianbin Ma2,§Hao Li1Derun Chen1Liang Mao1Leilei Yang1Tian Zhang2Wei Qiu2Zhigang Xu2( )Zhi-Jun Sun1 ( )
The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) & Key Laboratory of Oral Biomedicine Ministry of Education, School and Hospital of Stomatology, Wuhan University, Wuhan 430079, China
Key Laboratory of Luminescence Analysis and Molecular Sensing (Southwest University), Ministry of Education, School of Materials and Energy & Chongqing Engineering Research Center for Micro-Nano Biomedical Materials and Devices, Southwest University, Chongqing 400715, China

§ Junjie Zhou and Xianbin Ma contributed equally to this work.

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Graphical Abstract

To improve cancer immunotherapy by eliciting pyroptosis, we reasonably designed and constructed a nanoplatform (CANPs) integrating the heat shock protein 90 inhibitor tanespimycin (17-AAG) with the photosensitizer chlorin e6 (Ce6) to simultaneously target the tumor. CANPs efficiently boosted anti-tumor immune responses and suppressed tumor growth, thereby extending the survival of 4T1 breast tumors-bearing mice.

Abstract

Despite immunotherapy involving immune checkpoint inhibitors (ICIs) have revolutionized cancer therapy, the clinical efficacy is limited due to ICI resistance. Pyroptosis is a gasdermin-mediated programmed cell death that enhances responses to ICIs. However, nontargeted elicitation of pyroptosis may induce systemic side effects and toxicity. Therefore, we reasonably design and construct a tumor-specific prodrug that combines the heat shock protein 90 inhibitor tanespimycin (17-AAG) with the photosensitizer chlorin e6 (Ce6) to induce pyroptosis, by utilizing the high glutathione level in the tumor microenvironment. The released Ce6 and 17-AAG produce reactive oxygen species by laser triggering, which induces gasdermin E-mediated pyroptosis. Furthermore, 17-AAG reduces myeloid-derived suppressor cells and sensitizes tumors to anti-programmed death-1 (PD-1) therapy. Thus, our prodrug strategy achieves tumor-targeted pyroptosis to suppress tumor growth, thereby improving the response to anti-PD-1 therapy and extending the survival of 4T1 breast tumor-bearing mice. Consequently, this pyroptosis-based prodrug represents a novel strategy for enforcing immunogenic photodynamic therapy.

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Nano Research
Pages 3398-3408
Cite this article:
Zhou J, Ma X, Li H, et al. Inspired heat shock protein alleviating prodrug enforces immunogenic photodynamic therapy by eliciting pyroptosis. Nano Research, 2022, 15(4): 3398-3408. https://doi.org/10.1007/s12274-021-3946-2
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Received: 08 August 2021
Revised: 18 October 2021
Accepted: 24 October 2021
Published: 15 December 2021
©  Tsinghua University Press and Springer-Verlag GmbH Germany, part of Springer Nature 2021
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