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

Abstract

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 in vitro and in vivo 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.