A novel hierarchical targeting and controllable smart nanoparticles for enhanced in situ nuclear photodynamic therapy

Photodynamic therapy (PDT) is a promising and non-invasive treatment for various cancers. Although nuclear PDT has considerable therapeutic prospects, it is still hindered by the non-specific recognition of tumor tissues or the degradation of nuclear targeting cationic groups by enzymes in the blood. Herein, a hierarchical targeted and controlled release strategy is proposed by using folate-modified poly-β-cyclodextrin (poly-β-CD) as a nano-carrier for loading nuclear localization signals (NLSs)-conjugated photosensitizer PAP (PAP = pyropheophorbide a—PAAKRVKLD). Excitingly, the obtained FA-CD@PAP (FA = folic acid) and nanoparticles (NPs) can specifically recognize tumor cells overexpressing folate receptors (FR) to remarkedly enhance the intracellular accumulation. Furthermore, the encapsulated PAP can be released under acidic conditions to realize precise nuclear localization. The reactive oxygen species (ROS) generated by the intranuclear-accumulated PAP upon irradiation can oxidize and destroy DNA chains or DNA repair enzymes instantaneously, which can directly induce cell death. As a result, FA-CD@PAP NPs exhibit excellent tumor regression and negligible side effects. This work provides an intelligent nuclear-targeted delivery strategy for in situ nuclear PDT with extremely prominent efficacy and high biological safety.