Dual-Targeted Lipid Nanotherapeutic Boost for Chemo-Immunotherapy of Cancer

Seok Beom Yong, Srinivas Ramishetti, Meir Goldsmith, Yael Diesendruck, Inbal Hazan-Halevy, Sushmita Chatterjee, Gonna Somu Naidu, Assaf Ezra, Dan Peer

Research output: Contribution to journalArticlepeer-review

Abstract

Chemo-immunotherapy is a combination of “standard-of-care” chemotherapy with immunotherapy and it is considered the most advanced therapeutic modality for various types of cancers. However, many cancer patients still poorly respond to current regimen of chemo-immunotherapy and suggest nanotherapeutics as a boosting agent. Recently, heme oxygenase-1 (HO1) is shown to act as an immunotherapeutic molecule in tumor myeloid cells, in addition to general chemoresistance function in cancer cells suggesting that HO1-targeted therapeutics can become a novel, optimal strategy for boosting chemo-immunotherapy in the clinic. Currently the available HO1-inhibitors demonstrate serious adverse effects in clinical use. Herein, tumor myeloid cell- and cancer cell-dual targeted HO1-inhibiting lipid nanotherapeutic boost (T-iLNTB) is developed using RNAi-loaded lipid nanoparticles. T-iLNTB-mediated HO1-inhibition sensitizes cancer cells to “standard-of-care” chemotherapeutics by increasing immunogenic cell death, and directly reprograms tumor myeloid cells with distinguished phenotype. Furthermore, tumor myeloid cell reprogramming by T-iLNTB induces CD8+ cytotoxic T cell recruitment, which drives “Cold-to-Hot” transition and correlates with improved responsiveness to immune checkpoint inhibitor in combination therapy. Finally, ex vivo study proves that HO1-inhibition directly affects tumor macrophage differentiation. This study demonstrates the potential of T-iLNTB as a novel therapeutic modality for boosting chemo-immunotherapy.

Original languageEnglish
Article number2106350
JournalAdvanced Materials
Volume34
Issue number13
DOIs
StatePublished - 1 Apr 2022

Keywords

  • HO1-targeted nanotherapeutics
  • cancer-targeted therapy
  • chemo-immunotherapy
  • ionizable lipid nanoparticle
  • targeted lipid nanoparticle

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