A pyroptosis nanotuner for cancer therapy
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Binlong Chen1,2, Yue Yan2, Ye Yang2
1State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, China.
Abstract:
Pyroptosis is a gasdermin-mediated programmed necrosis that occurs via membrane perforation and that can be exploited for biomedical applications in cancer therapy. However, inducing specific pyroptotic cancer cell death while sparing normal cells is challenging. Here, we report an acid-activatable nanophotosensitizer library that can be used to spatiotemporally target distinct stages of endosomal maturation, enabling tunable cellular pyroptosis. Specific activation of phospholipase C signalling transduction in early endosomes triggers gasdermin-E-mediated pyroptosis, which is dramatically reduced when acid-activatable nanophotosensitizers are transported into late endosomes/lysosomes. This nanotuner platform induces pyroptotic cell death with up to 40-fold tunability in various gasdermin-E-positive human cancers, resulting in enhanced anti-tumour efficacy and minimized systemic side effects. This study offers new insights into how to engineer nanomedicines with tunable pyroptosis activity through specific targeting of distinct endocytic signalling for biomedical applications.
Insights
Researchers developed an acid-activatable nanophotosensitizer that precisely controls pyroptosis (programmed cell death) in cancer cells. This tunable approach enhances anti-tumor efficacy while minimizing side effects in gasdermin-E-positive cancers.
Area of Science:
- Biomedical Engineering
- Molecular Biology
- Oncology
Background:
- Pyroptosis, a form of programmed necrosis mediated by gasdermins, offers potential for cancer therapy but faces challenges in selectively targeting cancer cells.
- Inducing pyroptosis specifically in cancer cells while sparing healthy tissues remains a significant hurdle in developing effective cancer treatments.
Purpose of the Study:
- To engineer an acid-activatable nanophotosensitizer platform for spatiotemporally controlled pyroptosis.
- To investigate the role of endosomal maturation stages in modulating pyroptosis activity.
- To develop a tunable system for enhancing anti-tumor efficacy and reducing systemic side effects in cancer therapy.
Main Methods:
- Development of an acid-activatable nanophotosensitizer library.
- Targeting distinct stages of endosomal maturation (early endosomes vs. late endosomes/lysosomes).
- Activation of phospholipase C signaling transduction to trigger gasdermin-E-mediated pyroptosis.
Main Results:
- Demonstrated tunable pyroptosis induction with up to 40-fold control.
- Showcased reduced pyroptosis when nanophotosensitizers reached late endosomes/lysosomes.
- Achieved enhanced anti-tumor efficacy in gasdermin-E-positive human cancers with minimized systemic side effects.
Conclusions:
- The nanotuner platform enables precise control over pyroptosis through targeted endocytic signaling.
- This approach offers a promising strategy for developing nanomedicines with tunable pyroptosis for cancer therapy.
- The study provides insights into engineering nanomedicines for targeted cancer cell death.
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