Triple-synergistic anticancer therapy enabled by a multifunctional upconversion nanoplatform integrating cascade tumor starvation, chemodynamic, and photodynamic modalities

The development of multifunctional nanotherapeutics offers a promising strategy to overcome the inherent limitations of conventional cancer treatments. Herein, we report an upconversion nanoparticle (UCNP)-based nanoplatform, FUM-CFcG, rationally engineered for cascade combination therapy integrating starvation therapy (ST), chemodynamic therapy (CDT), and photodynamic therapy (PDT). The nanoplatform is constructed from multi-shell UCNPs exhibiting enhanced red emission under 808 nm near-infrared (NIR) irradiation and is surface-functionalized with folic acid–polyethylene glycol (FPEG) block copolymers for targeted tumor delivery. Glucose oxidase (GOx), ferrocene (Fc), and chlorin e6 (Ce6) are covalently conjugated to the nanocarriers through disulfide bonds, enabling glutathione (GSH)-responsive release within the reductive tumor microenvironment (TME). Upon cellular internalization, GOx catalyzes glucose oxidation to induce starvation while simultaneously generating hydrogen peroxide, which subsequently drives Fc-mediated Fenton-like reactions to produce highly cytotoxic hydroxyl radicals for CDT. Meanwhile, NIR-excited UCNPs activate Ce6 to generate singlet oxygen, enabling PDT. In vitro studies confirmed that FUM-CFcG exhibits efficient cellular uptake in folate receptor-overexpressing HeLa cells, elevated intracellular reactive oxygen species (ROS) generation, and pronounced synergistic cytotoxicity. Importantly, FUM-CFcG functions as a cascade system rather than a simple co-delivery platform, as GOx-mediated glucose depletion simultaneously generates H 2 O 2 to activate Fc-mediated CDT, while enhanced red upconversion emission under 808 nm irradiation enables Ce6-mediated PDT. This coupling of biochemical cascade amplification with NIR-responsive photodynamic activation represents a key design feature of the FUM-CFcG nanoplatform. Collectively, these findings demonstrate a UCNP-based strategy for targeted, GSH-responsive, and cascade-amplified multimodal cancer therapy.