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Background Photodynamic therapy (PDT), as a promising strategy in cancer treatment that utilizes photosensitizers (PSs) to produce reactive oxygen species (ROS), has been widely used for eliminating cancer cells under specific wavelength light irradiation. However, the low aqueous solubility of PSs, and special tumor environments (TME), such as high glutathione (GSH) and tumor hypoxia remain challenges towards PDT for hypoxic tumor treatment. Results To address these problems, we constructed a novel nanoenzyme (HMPC) for enhanced PDT-ferroptosis therapy by integrating small Pt nanoparticles (Pt NPs) and near-infrared photosensitizer CyI into iron-based metal organic frameworks (MOFs). In addition, hyaluronic acid (HA) was adhered to the surface of the nanoenzymes to enhance the targeting ability. In this design, MOFs act not only as a delivery vector for PSs, but also a ferroptosis inducer. Pt NPs stabilized into MOFs were functioned as an oxygen (O2) generator by catalyzing hydrogen peroxide (H2O2) into O2 to relieve tumor hypoxia and increase 1O2 generation. In vitro and in vivo results demonstrated that under NIR irradiation, HMPC could effectively relive the tumor hypoxia and decrease the level of GSH in TME, resulting in enhanced PDT-ferroptosis therapy against hypoxic tumor. Conclusion The proposed nanoenzymes represent an important advance in altering TME for improved clinical PDT-ferroptosis therapy, as well as their potential as effective theranostic agents for hypoxic tumors.

Introduction:Here, based on oxygen-dependent photodynamic therapy (PDT) and oxygen-consumed oxidative phosphorylation of cancer tissues, we designed and developed a nanosystem (named CyI&Met-Liposome, LCM) to co-encapsulate the photosensitizer CyI and mitochondrial respiration inhibitor metformin (Met) as a PDT enhancer. Methods: We synthesized nanoliposomes encapsulating Met and CyI with excellent photodynamic/photothermal and anti-tumor immune properties using a thin film dispersion method. Confocal microscopy and flow cytometry were used to assess the cellular uptake, PDT, photothermal therapy (PTT) and immunogenicity of nanosystem in vitro. Finally, two tumor models in mice were constructed to investigate the tumor suppression and immunity in vivo. Results:The resulting nanosystem relieved hypoxia in tumor tissues, enhanced PDT efficiency, and amplified antitumor immunity induced by phototherapy. As a photosensitizer, CyI effectively killed the tumor by generating toxic singlet reactive oxygen species (ROS), while the addition of Met reduced oxygen consumption in tumor tissues, thereby evoking an immune response via oxygenboosted PDT. Both in vitro and in vivo results illustrated that LCM effectively restricted the respiration of tumor cells to reduce tumor hypoxia, thus providing continuous oxygen for enhanced CyI-mediated PDT. Furthermore, T cells were recruited and activated at high levels, providing a promising platform to eliminate the primary tumors and synchronously realize effective inhibition of distant tumors.