Necroptosis, caspase-independent programmed necrosis, has emerged as a therapeutic target to make dying cancer cells stimulants for antitumor immune responses. The clinical translations exploiting necroptosis, however, have been limited since most cancer cells downregulate receptor-interacting protein kinase 3 (RIPK3) as a key enzyme for necroptosis. Herein, nanobubbles (NBs) that can trigger RIPK3-independent necroptosis, facilitating cell-membrane rupture via the acoustic cavitation effect are reported. The NBs, imbibing perfluoropentane as the gas precursor, are prepared using an amphiphilic polymer conjugate, composed of PEGylated carboxymethyl dextran as the hydrophilic backbone and chlorin e6 as the hydrophobic sonosensitizer. When exposed to ultrasound, the NBs efficiently promote the release of biologically active damage-associated molecular patterns by inducing burst-mediated cell-membrane disintegration. Consequently, the necroptosis-inducible NBs significantly improve antitumor immunity by maturation of dendritic cells and activation of CD8+ cytotoxic T cells both in vitro and in vivo. In addition, the combination of NBs and immune checkpoint blockade leads to complete regression of the primary tumor and beneficial therapeutic activity against metastatic tumors in an RIPK3-deficient CT26 tumor-bearing mouse model. Overall, the innovative NB that causes immunogenic cell death of cancer via RIPK3-independent necroptosis is a promising enhancer for cancer immunotherapy.
Bibliographical noteFunding Information:
W.U. and H.K. contributed equally to this work. This work was financially supported by the Industrial Technology Innovation Program (10078392) funded by the Ministry of Trade, Industry and Energy (MOTIE, Korea) and the Basic Science Research Programs (20100027955, 2018R1A2B3006080, and 2018R1D1A1B07047950) of the National Research Foundation (NRF), Republic of Korea. CT26 and HT29 cells were purchased from ATCC (MD, USA). BMDCs were harvested from 8-week-old BALB/c mice. All of the animal studies were performed with the approval of the Institutional Animal Care and Use Committee (IACUC) at the Korea Institute of Science and Technology and in compliance with the institutional guidelines of IACUC.
© 2020 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
- damage-associated molecular patterns
- immune checkpoint blockade
- reactive oxygen species
- sonodynamic therapy
ASJC Scopus subject areas
- General Materials Science
- Mechanics of Materials
- Mechanical Engineering