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‐1β/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.