A new type of photosensitizers used in photodynamic therapy, which is based on photon upconverting nanoparticles, is reported. These photosensitizers are excitable with infrared irradiation, which has several times larger tissue penetration depth than the currently available ones. They are brought close to the target cancer cells through antigen-antibody interaction with good specificity and versatility. The design is also flexible in that various photosensitive molecules can be potentially adopted into the design. Results from in vitro experiments demonstrate their promise of becoming the next generation photodynamic therapy drugs.Photodynamic therapy (PDT) is gaining acceptance as a technique for cancer treatment in recent years. [1][2][3] PDT utilizes a photosensitizer, working as a light-sensitive drug, to treat the target tissue locally upon the irradiation of light with appropriate wavelengths. It is generally accepted that the mechanism of PDT is based on the interaction between the excited photosensitizer and surrounding molecules, generating reactive oxygen species (ROS), such as singlet oxygen. ROS can cause oxidative damage to biological substrates and ultimately cell death. One of the key components in effective and efficient PDT is the photosensitizers, also called PDT drugs. Features most desired for an ideal PDT drug include: 1) Be specific to the target tissue; 2) Have a high photochemical reactivity, i.e., can effectively produce ROS when exposed to appropriate irradiation; 3) Exhibit little toxicity in the dark; and 4) Can be excited at a wavelength in the region where tissue penetration of irradiation is at a maximum. Here we report the design of a type of versatile photosensitizers, which could potentially satisfy all the above requirements and become the next generation PDT drugs, based on photon upconverting nanoparticles (PUNPs).Photon upconverting materials convert lower-energy light to higher-energy light through excitation with multiple photons. They have been widely used for some time in such applications as display, bioassay, and bioimaging, to name a few. [4] In this application, we take advantage of the fact that such materials would adsorb infrared irradiation and emit visible light to further excite the photosensitizing molecules. The particles of nanometer size would also facilitate the delivery and excretion of the proposed photosensitizer as PDT drug.The optimal spectral window for biological tissue penetration of irradiation is around 800 nm to 1 μm. Yet, single photons with infrared wavelengths are usually energetically too low for singlet oxygen generation. Multiphoton excitation using infrared light as irradiation source has been proposed and explored. [5][6][7][8][9] The new design of versatile PDT photosensitizers we propose is schematically shown in Figure 1. PUNPs are first coated with a porous, thin layer of silica. During the coating process, photosensitizing molecules with high absorbance in the spectral window matching the emission of the PUNPs are doped, ...