Targeting photodynamic and photothermal therapy to the endoplasmic reticulum enhances immunogenic cancer cell death

Wei Li,Jie Yang,Bing Qin,Yan Lou,Mengshi Jiang,Zhenyu Luo,Lihua Luo,Yongzhong Du,Jian You,Xiaoling Yuan,Qingpo Li,Junlei Zhang,Hang Yin,Yunqing Qiu,Chunqi Zhu

doi:10.1038/s41467-019-11269-8

Wei Li, Jie Yang + Show 13 more

Open Access

https://doi.org/10.1038/s41467-019-11269-8

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Abstract

Immunogenic cell death (ICD)-associated immunogenicity can be evoked through reactive oxygen species (ROS) produced via endoplasmic reticulum (ER) stress. In this study, we generate a double ER-targeting strategy to realize photodynamic therapy (PDT) photothermal therapy (PTT) immunotherapy. This nanosystem consists of ER-targeting pardaxin (FAL) peptides modified-, indocyanine green (ICG) conjugated- hollow gold nanospheres (FAL-ICG-HAuNS), together with an oxygen-delivering hemoglobin (Hb) liposome (FAL-Hb lipo), designed to reverse hypoxia. Compared with non-targeting nanosystems, the ER-targeting naosystem induces robust ER stress and calreticulin (CRT) exposure on the cell surface under near-infrared (NIR) light irradiation. CRT, a marker for ICD, acts as an ‘eat me’ signal to stimulate the antigen presenting function of dendritic cells. As a result, a series of immunological responses are activated, including CD8+ T cell proliferation and cytotoxic cytokine secretion. In conclusion, ER-targeting PDT-PTT promoted ICD-associated immunotherapy through direct ROS-based ER stress and exhibited enhanced anti-tumour efficacy.

Highlights

Immunogenic cell death (ICD)-associated immunogenicity can be evoked through reactive oxygen species (ROS) produced via endoplasmic reticulum (ER) stress
To enable ER targeting of ICG-HAuNS, a peptide named FAL. Then NH2-DSPE-PEG2000 (FAL) was conjugated to the particle using NH2-PEG-thioctic acid (TA) as a linker. 1H nuclear magnetic resonance was performed to verify the chemical structures of different compounds
Induction of ICD presents a therapeutic modality for cancer treatment, which is attributed to its ability of allowing the immune system to eradicate cancer cells through a “bystander effect”[33,34]

Summary

Introduction

Immunogenic cell death (ICD)-associated immunogenicity can be evoked through reactive oxygen species (ROS) produced via endoplasmic reticulum (ER) stress. We generate a double ER-targeting strategy to realize photodynamic therapy (PDT) photothermal therapy (PTT) immunotherapy This nanosystem consists of ER-targeting pardaxin (FAL) peptides modified-, indocyanine green (ICG) conjugated- hollow gold nanospheres (FAL-ICGHAuNS), together with an oxygen-delivering hemoglobin (Hb) liposome (FAL-Hb lipo), designed to reverse hypoxia. ER-targeting PDT-PTT promoted ICD-associated immunotherapy through direct ROS-based ER stress and exhibited enhanced anti-tumour efficacy. NIR light (808 nm) mediated PTT/PDT in ER under sufficient oxygen supply induced robust ROS-based ER stress, characterized by upregulation of CHOP (C/EBP-homologous protein-10; an ER apoptotic protein). We have built double “ER missiles”, which could be used for PTT/PDT and for ICD-associated cancer immunotherapy through induction of specific ER stress under the control of near infrared (NIR) light

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Results

Conclusion