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Photodynamic therapy(PDT)is a well-established modality for cancer therapy,which locally kills cancer cells when light irradiates a photosensitizer.However,conventional PDT is often limited by the extremely short lifespan and severely limited diffusion distance of reactive oxygen species(ROS)generated by photosensitizer,as well as the penetration depth of visible light activation.We develop a near-infrared(NIR)triggered nanophotosensitizer based on mitochondria targeted titanium dioxide-coated upconversion nanoparticles for PDT against cancer.When irradiated by NIR laser,the nanophotosensitizer could produce ROS in mitochondria,which induced the domino effect on ROS burst.The overproduced ROS accumulated in mitochondria,resulting in mitochondrial collapse and irreversible cell apoptosis.On the other hand,photodynamic therapy against multidrug resistant cancer is limited seriously due to the efflux of photosensitizer molecules by P-glycoprotein,which leads to insufficient production of ROS.For the purpose of abundant ROS generation and effective therapeutic response,we firstly design and fabricate a nuclear targeted dual-photosensitizer for photodynamic therapy against multidrug resistant cancer.Molecule-photosensitizer Ce6 was modified on the surface of core/shell structure nano-photosensitizer upconversion@TiO2 and then nuclear targeted peptides TAT were anchored for nuclear targeting.Through selective doping of rare earth elements,multiple ROS(˙OH,O2˙‐,and 1O2)can be generated and realize their functions synergistically using a single 980 nm NIR excitation.The nano-sized photosensitizer accompanied with nuclear targeting can effectively generate multiple ROS in the nucleus regardless of P-glycoprotein and directly break DNA double strands.