“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 can-cer photodynamic therapy(PDT):(i)the hypoxic tumor microenvironment(TME);(ii)low generation efficiency of toxic reactive oxygen species(ROS)in aggre-gates 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 nanoengi-neering strategy is demonstrated:a photodynamic nanoplatform U-Ir@PAA-ABS based on the covalent combination of lanthanide-doped upconversion nanoparti-cles(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 ferropto-sis.Taken together,the in vitro and in vivo results demonstrate a successful strategy for improving the efficacy of PDT against hypoxic tumors.