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Dual-stimulus phototherapeutic nanogel for triggering pyroptosis to promote cancer immunotherapy
Jiming Xu1, Wei Qiu1, Mengyun Liang1
1Key Laboratory of Luminescence Analysis and Molecular Sensing, Ministry of Education, School of Materials and Energy & Chongqing Engineering Research Center for Micro-Nano Biomedical Materials and Devices, Southwest University, Chongqing 400715, PR China.
Abstract:
Pyroptosis is a highly inflammatory programmed cell death that activates inflammatory response, reverses immunosuppression and promotes systemic immune response for solid tumors treatment. However, the uncontrollable and imprecise process of pyroptosis stimulation leads to a scanty therapeutic effect. Here, we report a GSH/ROS dual response nanogel system (IMs) that can actively target the overexpressed mannose receptor (MR) of cancer cells, serve ultra-stable photothermal capacity of indocyanine green (ICG), induce cell pyroptosis and achieve enhanced tumor immune response. Photo-triggered IMs induce cytoplasmic Ca2+ introgression and activate caspase-3 through photo-activated ICG. The disconnect of SeSe bonds can break the oxidation and reduction balance of tumor cells, causing oxidative stress and synergistically enhancing caspase-3 cleavage, and regulating cell pyroptosis ultimately. Combined with anti-programmed death receptor 1 (anti-PD-1), the nanogel system not only effectivly suppress both primary tumor and distance tumor but also prolong the survival period of mice. This work introduces a strategy to optimize the photothermal performance of ICG and enhances tumor immune response mediated by triggering pyroptosis, which provides an impressive option for immune checkpoint blockade therapy.
Insights
This study introduces a novel nanogel system that precisely triggers pyroptosis (programmed cell death) in cancer cells. This approach enhances anti-tumor immunity and improves outcomes when combined with immune checkpoint blockade therapy.
Area of Science:
- Biomedical Engineering
- Immunology
- Materials Science
Background:
- Pyroptosis is a programmed cell death pathway crucial for anti-tumor immunity but challenging to control therapeutically.
- Current pyroptosis induction methods lack precision, limiting their clinical efficacy in solid tumor treatment.
Purpose of the Study:
- To develop a dual-responsive nanogel system for targeted pyroptosis induction and enhanced anti-tumor immune response.
- To optimize photothermal properties and synergistically trigger pyroptosis via oxidative stress.
Main Methods:
- A GSH/ROS dual-responsive nanogel system (IMs) was designed, incorporating indocyanine green (ICG) for photothermal therapy.
- The nanogel was engineered to target mannose receptors (MR) on cancer cells and photo-triggered to induce pyroptosis.
- The system's efficacy was evaluated in combination with anti-programmed death receptor 1 (anti-PD-1) therapy in vivo.
Main Results:
- The IMs system demonstrated targeted delivery, enhanced photothermal stability, and effective induction of pyroptosis via Ca2+ influx and caspase-3 activation.
- Disruption of the oxidation-reduction balance by SeSe bond cleavage further potentiated pyroptosis.
- Combined therapy significantly suppressed primary and distant tumors and prolonged survival in mice.
Conclusions:
- The developed nanogel system offers a precise strategy for triggering pyroptosis and potentiating anti-tumor immunity.
- This approach enhances the effectiveness of immune checkpoint blockade therapy, presenting a promising option for cancer treatment.
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