Biodegradable Monometallic Aluminum as a Biotuner for Tumor Pyroptosis

Pyroptosis is an effective anti-tumor strategy. However, monometallic pyroptosis biotuners have not been explored until now. Here, we discover for the first time that biodegradable monometallic Al can act as a pyroptosis biotuner for tumor therapy. pH-sensitive Al nanoparticles (Al@P) are obtained by equipping polyethylene glycol-b-(poly(methyl methacrylate)-co-poly(4-vinylpyridine), which can exert their effect at the tumor site without affecting normal cells. The H2 and Al3+ release by Al@P in the acidic environment of tumors disrupts the redox balance and ionic homeostasis in tumor cells, thus generating large amounts of reactive oxygen species (ROS), leading to caspase-1 activation, gasdermin D cleavage, and IL-1 beta/LDH release, which induces canonical pyroptotic death. Meanwhile, the prodrug Doxorubicin (Pro-DOX) is successfully loaded onto Al@P (Al@P-P) and can be activated by ROS to release DOX in the tumor cells, thus further improving the tumor-killing efficiency. Ultimately, Al@P-P is degradable and exhibits efficient tumor inhibition. Biodegradable monometallic Al is used for the first time as a pyroptosis biotuner for tumor therapy. Al reacts with H+ to form H2 and Al3+, which not only remodels the TME but also enables its degradation. H2 and Al3+ disrupt redox balance and ionic homeostasis, inducing the generation of abundant ROS, which activates ROS-responsive prodrugs, ultimately achieving efficient tumor therapy. image