Near-infrared-activated photothermal/chemodynamic/nitric-oxide synergistic tumor therapy by Fe-PDA/BNN6@GelMA hydrogel microspheres

The development of integrated multimodal synergistic therapy platforms is pivotal for advancing cancer treatment, particularly in overcoming challenges such as tumor heterogeneity and resistance to single treatments. In this paper, we present microfluidic-engineered Fe-PDA/BNN6@GelMA hydrogel microspheres (Fe-PDA/BNN6@GMs) as an all-in-one platform for near-infrared (NIR)-activated synergistic cancer therapy. This multifunctional platform consists of polydopamine (PDA)-coordinated Fe(II) nanoparticles loaded with the nitric oxide (NO) donor BNN6 and embedded in a gelatin methacryloyl (GelMA) hydrogel matrix. The flower-like Fe-PDA nanoparticles provide abundant reactive sites for the immobilization of BNN6 via π–π stacking. Upon NIR irradiation, the Fe-PDA nanoparticles generate localized hyperthermia, which directly induces tumor ablation and enhances Fe(II)-mediated chemodynamic therapy to generate cytotoxic reactive oxygen species (ROS). Simultaneously, the photothermal heating facilitates the controlled release of NO from BNN6, which promotes tumor apoptosis and interacts with ROS to form highly cytotoxic reactive nitrogen species (RNS), further amplifying the therapeutic effect. The GelMA matrix ensures stable retention and sustained local delivery of therapeutic agents at the tumor site, minimizing systemic toxicity. This tri-modal interplay of photothermal, chemodynamic, and gas therapies achieves efficient tumor eradication in MCF-7 tumor-bearing mice, offering a versatile strategy for injectable multifunctional hydrogels for synergistic cancer therapy.