“Three birds with one stone” nanoplatform: Efficient near-infrared-triggered type‑I AIE photosensitizer for mitochondria-targeted photodynamic therapy against hypoxic tumors

Currently three major problems seriously limit the practical application of cancer photodynamic therapy (PDT): (i) the hypoxic tumor microenvironment (TME); (ii) low generation efficiency of toxic reactive oxygen species (ROS) in aggregates and (iii) shallow tissue penetration depth of excitation light. Very limited approaches are available for addressing all the above three problems with a single design. Herein, a rational “three birds with one stone” molecular and nanoengineering strategy is demonstrated: a photodynamic nanoplatform U-Ir@PAA-ABS based on the covalent combination of lanthanide-doped upconversion nanoparticles (UCNPs) and an AIE-active dinuclear Ir(III) complex provides a low oxygen concentration-dependent type-I photochemical process upon 980 nm irradiation by Föster resonance energy transfer (FRET). U-Ir@PAA-ABS targets mitochondria and has excellent phototoxicity even in severe hypoxia environments upon 980 nm irradiation, inducing a dual-mode cell death mechanism by apoptosis and ferroptosis. Taken together, the in vitro and in vivo results demonstrate a successful strategy for improving the efficacy of PDT against hypoxic tumors.