An ATP-activated self-cascade nanoplatform for ROS/mPTT/starvation tri-therapy through tumor microenvironment remodeling

Iron-gallic acid chelate nanoparticles (Fe-GA NPs) have emerged as promising Fenton catalysts and drug carriers in oncology. However, their therapeutic efficacy remains constrained by tumor microenvironment (TME) limitations - suboptimal pH and insufficient endogenous hydrogen peroxide. To overcome these barriers, we engineered an ATP-responsive core-shell nanoarchitecture (GOx@Fe-GA) integrating glucose oxidase (GOx) with Fe-GA coordination networks. Upon encountering elevated ATP concentrations in tumor cells, the nanosystem undergoes programmed disassembly: released GOx depletes glucose to induce metabolic starvation while generating substantial H₂O₂ and acidifying the TME, thereby creating ideal conditions for Fe-GA-mediated Fenton reactions. Simultaneously, Fe-GA acts as a photothermal agent under near-infrared irradiation, leading to mild hyperthermia that synergizes with reactive oxygen species (ROS) to overcome thermotolerance by disrupting heat shock protein (HSP70) defenses. Both <i>in vitro</i> and <i>in vivo</i> studies showed potent tumor suppression with minimal systemic toxicity. These studies establish GOx@Fe-GA as a self-enhancing therapeutic platform. Here, tumor-specific ATP triggers a cascading therapeutic amplification involving an ROS storm, metabolic deprivation, and photothermal sensitization.