Novel drug-free cascaded nanoparticles induce tumor-specific ROS storms via multimodal synergistic anticancer therapy.

Reactive oxygen species (ROS), generated by sonosensitizers, play a pivotal role in tumor cell apoptosis during sonodynamic therapy (SDT), particularly for tumors located deep within tissues. Nevertheless, conventional sonosensitizers present limitations including inadequate ROS generation, insufficient tumor-specific accumulation, and associated adverse effects, significantly restricting their clinical applicability. To address these limitations, novel drug-free multifunctional nanoparticles (designated HGMP NPs) were synthesized. These NPs consist of mesoporous polydopamine (MPDA)-loaded protoporphyrin IX (PpIX), further surface-modified with glucose oxidase (GOx) and hyaluronic acid (HA), to achieve integrated photothermal, sonodynamic, and starvation-based tumor therapy. Upon exposure to near-infrared (NIR) irradiation (808 nm) combined with ultrasound (US), HGMP NPs exhibited pronounced synergistic anticancer effects. Specifically, the photothermal effect triggered by NIR irradiation effectively enhanced local oxygen supply within tumor sites, thus significantly augmenting ROS production and improving the therapeutic outcomes of SDT. Concurrently, GOx-mediated glucose depletion induced tumor starvation and produced hydrogen peroxide (H2O2), further exacerbating oxidative stress within the tumor microenvironment. Transcriptomic analysis revealed that ROS and TNF signaling pathways represented key mechanisms underlying tumor elimination by this multimodal synergistic strategy. Real-time PCR analysis and ELISA assays further validated activation of the TNF signaling pathway. Importantly, this study first confirmed the high biocompatibility and biosafety of HGMP NPs via serum metabolomics, demonstrating no detectable systemic metabolic perturbations. Collectively, the prepared HGMP NPs provide a rational paradigm for synergistic anticancer therapy. These findings highlight the potential of HGMP NPs as an exceptionally safe and effective nanoplatform for cancer treatment, offering valuable insights into future developments in cancer nanomedicine.