Intranuclear photosensitizer delivery and photosensitization for enhanced photodynamic therapy with ultralow irradiance

Photodynamic therapy (PDT) is a well-established clinical treatment modality for various diseases. However, reactive oxygen species (ROS) generated by photosensitizers(PS) under proper irradiation exhibits the extremely short life span (<200 ns) and severely limited diffusion distance (20 nm), so the damage of ROS to biomolecules, especially DNA, is strongly confined to the immediate vicinity of ROS generation. In this report, an effi cient nucleartargeted delivery strategy is proposed by using TAT and RGD peptides co-conjugated mesoporous silica nanoparticles (MSNs) as PS carriers. The conjugation of TAT peptides enable the nuclear penetration of MSNs for effi - cient accumulation of PS inside nuclei. The intranuclear-accumulated PS can generate ROS upon irradiation right inside nuclei to destroy DNA instantaneously. For the purpose of in vivo applications, the co-conjugated RGD peptides endow the nuclear-targeted delivery system with specifi c binding and recognition to tumor vasculature and tumor cell membranes for signifi cantly enhanced specifi city and reduced side effects. Through intravenous injection of these nanosystems in tumor-bearing mice at a rather low PS dose of 2 mg/kg, tumor growth is effi ciently inhibited by an extremely low irradiation dose of 6 J/cm ₂ . This work presents a new paradigm for specifi c PDT with high effi cacy and low side effects in vivo.