Necroptosis-Inducible Polymeric Nanobubbles for Enhanced Cancer Sonoimmunotherapy

Wooram Um, Hyewon Ko, Dong Gil You, Seungho Lim, Gijung Kwak, Man Kyu Shim, Suah Yang, Jeongjin Lee, Yeari Song, Kwangmeyung Kim, Jae Hyung Park

Research output: Contribution to journalArticlepeer-review

89 Citations (Scopus)


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.

Original languageEnglish
Article number1907953
JournalAdvanced Materials
Issue number16
Publication statusPublished - 2020 Apr 1


  • damage-associated molecular patterns
  • immune checkpoint blockade
  • necroptosis
  • reactive oxygen species
  • sonodynamic therapy

ASJC Scopus subject areas

  • Materials Science(all)
  • Mechanics of Materials
  • Mechanical Engineering


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