A Chloroplast-Inspired Theranostic Nanoplatform for Self-Sustaining Oxygen-Elevating Photodynamic Therapy and Glutathione-Triggered Carbon-Centered Radical Synergistic Therapy

Abstract

Abstract Achieving precise drug delivery to the tumor site can minimize systemic side effects caused by off-target effects. As a therapy that depends on oxygen content, photodynamic therapy (PDT) is significantly constrained by the hypoxic nature of the tumor microenvironment (TME). Compared with the limited efficacy of single PDT, the combination of multiple treatment modalities can achieve synergistic enhancement and superior therapeutic outcomes. Since carbon radical therapy does not rely on oxygen as a reactive substrate, it is mechanistically complementary to oxygen-dependent PDT. In this work, we report a novel strategy for developing a theranostic nanoplatform for long-lasting PDT activated by 1530 nm laser irradiation and glutathione (GSH)-triggered carbon-centered radical synergistic therapy that responds specifically to the TME. This theranostic nanoplatform (UCNPs@WOR:AF@CDC, UWAC) comprises three components: GSH-responsive engineered vesicles (CDC), functionalized metal-organic frameworks (WOR) encapsulating lanthanide upconversion nanoparticles (UCNPs@WOR, UW), and carbon radical prodrugs (ART-Fe, AF). Lanthanide-based upconversion nanoparticles (UCNPs) could upconvert 1530 nm light to 1390 nm for attenuation-minimized second near-infrared (NIR-II) fluorescence imaging and to visible light that serves as the light source for photocatalysis for water oxidation. The 1530 nm light-activated generation of reactive oxygen species (ROS), enhanced by UW-mediated hydrolytic oxygen evolution, works in synergy with the GSH-triggered release of the carbon radical prodrug (AF) to achieve long-lasting therapeutic outcomes. Importantly, it could achieve tumor-specific drug release, triggered by the degradation of the engineered vesicles in response to elevated GSH levels. This work develops a novel theranostic nanoplatform, which could achieve GSH-activated drug delivery, deep-tissue penetration, and a long-lasting therapeutic effect.