The next Frontier of photodynamic therapy: nuclear-targeted small-molecule photosensitizers for precise tumor cell elimination.

A photosensitizer (PS), which can generate reactive oxygen species (ROS) under laser irradiation, is a decisive factor in the efficacy of PDT. However, the ROS generated by PS has a short lifetime (<40 ns) and a small diffusion distance (<20 nm), which limits its effectiveness in PDT. Therefore, the location of PS in cells is a key factor affecting PDT outcomes. Organelles should be considered an important factor in determining the optimal required distance for PDT. Among organelles, the nucleus, as the "brain" of cells, is responsible for genetics and metabolism and is also the site of action for many anticancer drugs. Therefore, nucleus-targeted PDT is lethal to cells. Nucleus-targeted PS can not only more accurately block signaling pathways and inhibit tumor cell growth, but also delay tumor cell drug resistance by directly targeting genetic material or repair mechanisms. This review discusses the binding mode between nucleus-targeted PS and DNA, the mechanism of nuclear targeting, and the applications of nucleus-targeted PS. It also emphasizes the potential applications and challenges of nucleus-targeted PS. Overall, nucleus-targeted PS could be a promising tool for advancing PDT and improving its clinical applicability.