Optimization of multifunctional NaYbF₄:Er³⁺ upconversion nanoparticle-based dual drug delivery system for enhanced chemo-photodynamic therapy in prostate cancer

Upconversion efficiency in heterostructure hosts is critical for multicolor emission in biomedical applications, where cellular uptake is dependent on particle size. In chemo-photodynamic therapy (chemo-PDT), reducing cellular glutathione (GSH) levels through reactive nitrogen species (RNS) generation, combined with reactive oxygen species (ROS), offers a dual strategy to halt cancer cell proliferation. Herein, We optimized NaYbF₄:Er³⁺ upconversion nanoparticles (UCNPs) with size control (final nanocapsule size: 60.5 nm) and applied heterogeneous NaGdF₄:Yb³⁺,Er³⁺ and inert NaGdF₄ shelling, achieving a 30-fold enhancement in fluorescence intensity at 520 nm and 545 nm, alongside improved magnetic resonance imaging (MRI) efficacy. These core@shell@shell UCNPs were nano-precipitated with O²-(2,4-dinitrophenyl)-1-[(4-ethoxycarbonyl)piperazin-1-yl]diazen-1-ium-1,2-diolate a class of diazeniumdiolate prodrug and AIEgen molecule to form nanocapsules that generate reactive oxygen and nitrogen species (RONS). Under 980 nm NIR laser (0.25 W/cm²) and white light (0.5 W/cm²) irradiation, these nanocapsules deplete GSH to produce nitric oxide (NO), while AIEgen generates superoxide (∙O₂^-) and hydroxyl (•OH) radicals via type-I PDT, with NO and ∙O₂^- forming peroxynitrite (OONO^-). In LNCaP prostate cancer cells, 99.7 % nanocapsule internalization occurred within 1 h, and a low dose of 0.625 µg/mL achieved near-complete cell death under dual irradiation, demonstrating synergistic chemo-PDT efficacy. This dual drug delivery system, combining enhanced fluorescence, MRI, and RONS generation, holds promise for precise bioimaging and effective prostate cancer therapy.