Celastrol-Loaded Zwitterionic Nanogels Trigger Pyroptosis for Potent Antitumor Effects.

Pyroptosis has recently emerged as a promising therapeutic strategy owing to its unique advantages in inducing lytic cell death and eliciting immunogenic responses. Moderate induction of pyroptosis not only directly eliminates cancer cells but also activates antitumor immunity through the release of tumor-associated antigens and proinflammatory cytokines. However, most available pyroptosis inducers suffer from poor solubility, instability, and nonspecific biodistribution, which significantly hinder their translational potential. To address these challenges, we developed a pyroptosis-inducing delivery platform based on carboxybetaine zwitterionic nanogels for the efficient encapsulation of celastrol. These zwitterionic nanogels exhibit excellent resistance to protein adsorption and prolonged circulation in vivo. Upon drug release, celastrol promotes mitochondrial reactive oxygen species (ROS) accumulation, activates the caspase-3/GSDME axis, and triggers pyroptosis accompanied by immunogenic signals, including adenosine triphosphate (ATP) secretion, lactate dehydrogenase (LDH) release, and calreticulin (CRT) exposure. When combined with the anti-PD-1 checkpoint blockade, this platform further enhances dendritic cell maturation and antigen presentation, thereby amplifying pyroptosis-driven immune responses. In summary, our study demonstrates an effective strategy for inducing pyroptosis by integrating zwitterionic nanogel-mediated celastrol delivery with immune checkpoint inhibition, providing new insights and potential breakthroughs for cancer immunotherapy.