Celastrol-Loaded Zwitterionic Nanogels Trigger Pyroptosis for Potent Antitumor Effects
Shaoqi Sheng1, Jiaxin Zhang1, Licheng Yang1
1State Key Laboratory of Molecular Engineering of Polymers, Department of Macromolecular Science, Fudan University, Shanghai 200433, China.
ACS Applied Bio Materials
|December 29, 2025
Summary
This study developed zwitterionic nanogels to deliver celastrol, enhancing pyroptosis (programmed cell death) for cancer therapy. This approach improves drug delivery and boosts anti-tumor immunity when combined with immune checkpoint inhibitors.
Area of Science:
- Biomedical Engineering
- Cancer Immunology
- Nanotechnology
Background:
- Pyroptosis, a lytic cell death pathway, shows promise in cancer therapy by eliminating cancer cells and activating antitumor immunity.
- Current pyroptosis inducers face challenges like poor solubility, instability, and nonspecific biodistribution, limiting their clinical application.
Purpose of the Study:
- To develop an advanced drug delivery platform for efficient pyroptosis induction.
- To overcome the limitations of existing pyroptosis inducers for enhanced cancer immunotherapy.
Main Methods:
- Developed carboxybetaine zwitterionic nanogels for encapsulating celastrol.
- Investigated the nanogels' in vivo behavior, including protein adsorption resistance and circulation time.
- Assessed celastrol-induced pyroptosis and associated immunogenic signals (ROS, caspase-3/GSDME, ATP, LDH, CRT).
- Evaluated the combined effect of the nanogel platform and anti-PD-1 checkpoint blockade on immune responses.
Main Results:
- Zwitterionic nanogels demonstrated excellent stability and prolonged circulation in vivo.
- Celastrol released from nanogels effectively induced pyroptosis via ROS accumulation and caspase-3/GSDME activation.
- The treatment triggered significant immunogenic signals, indicating effective cell death and immune activation.
- Combination therapy with anti-PD-1 enhanced dendritic cell maturation and antigen presentation, amplifying anti-tumor immunity.
Conclusions:
- Zwitterionic nanogel-mediated celastrol delivery is an effective strategy for inducing pyroptosis and enhancing cancer immunotherapy.
- The developed platform overcomes limitations of traditional inducers, offering potential for clinical translation.
- Integration with immune checkpoint inhibition amplifies pyroptosis-driven immune responses, providing a novel approach for cancer treatment.
