Tumor microenvironment-responsive multifunctional nanoplatform with selective toxicity for MRI-guided photothermal/photodynamic/nitric oxide combined cancer therapy

The trade-off in nanomaterials-based cancer therapy between safety and therapeutic efficacy remains a significant challenge to overcome in the long run. In this context, we have designed a tumor microenvironment (pH, H2O2)-responsive multifunctional nanoplatform with a core–shell structure (C/B@M) for magnetic resonance imaging (MRI)-guided photothermal (PTT) /photodynamic (PDT) /nitric oxide (NO) combined cancer therapy. The pH/H2O2-responsive MnO2 coating not only shields from light, preventing the premature release of singlet oxygen, which is non-specifically toxic, but also generates O2 to alleviate tumor hypoxia, enhancing PDT efficacy. The degradation of MnO2 to Mn2+ aids in precise tumor localization for MRI-guided irradiation, thereby reducing the risk of inadvertent damage to normal cells. Once the shell is degraded within the tumor, the covalent organic framework (COF) core, crafted from porphyrin, produces singlet oxygen and thermal effects upon exposure to infrared light irradiation (660 nm). Concurrently, BNN6 decomposes under photothermal stimulation, releasing NO for gas therapy, which further ameliorates the tumor's hypoxic microenvironment, enabling MRI imaging-guided multimodal combined tumor treatments. The introduced C/B@M, with its selective toxicity, offers a novel approach to designing multifunctional nanoplatforms, addressing the intrinsic balance between safety and tumor-killing efficacy.