## 5 aPDT Performance in Clinical Studies
Opposingly, the other three studies using methylene blue used low concentrations, but the time of irradiation was increased, resulting in some positive outcomes because of using aPDT intervention. Some of the studies did not report the amount of energy density, explaining the results more difficult as the aPDT effect depends on the dosimetry of aPDT [33]. Considering aPDT dosimetry, it was critical to observe how these studies reported energy density delivered to the target area. In the reported studies, fiber optics were used to irradiate the canal's working length level. Logically, the light distribution among the fiber is not similar, resulting in different energy density values at various locations inside the root canal system. Only one study reported the energy density dose as a range [52]. Some of the reported studies applied aPDT as an independent intervention [51; 52]. It is also essential to consider aPDT as an adjunctive treatment. More importantly, future studies may attempt to explore the standardization of aPDT dosimetry and new strategies to enhance the disinfection outcomes. Nanostructures-Based Photosensitizers (PSs) to Overcome the Drawback of Conventional Endodontic Therapy: Present and Future Approaches  
Bio-nanotechnology has opened new avenues for aPDT. Two significant shortcomings of the current phototherapeutic interventions for the disinfection of root canals are the restricted penetration of photosensitizer (PS) and light propagation inside the dental tubules [36]. Extensive laboratory studies have shown that an essential aspect of this therapy is that the two components, when used independently, produce no effect on bacteria or healthy tissue. It is only the combination of PS and light that affects the bacteria [33]. Facing the paucity of delivery strategies to target sites, advances in photonanomedicine strategies have conveyed optimization and feasibility of the clinical outcomes of photodynamic therapy in medicine and biotechnology [58]. Nanoparticles associated with aPDT have greatly enhanced bacterial disinfection outcomes. Nanoparticles (1-100 nm in size) represent emergent PS carriers that show great promise for aPDT. They present the three dimensions in nanoscale and can be organic, inorganic, or combined [59]. Among these structures, polymeric-based nanocapsules and nanospheres and metallic and oxide nanoparticles can be found. In endodontics, the use of nanoparticles for aPDT has also gained interest. Conventional aPDT, as aforementioned, is based on the use of biocompatible PS applied in a specific site and photoactivated to generate ROS, decreasing microorganisms' viability. MB and TBO are well-recognized PS due to their lack of cytotoxicity and targeting ability against Gram-positive and Gram-negative bacteria [60]. However, the incomplete destruction of biofilms along the root canal using MB as the main PS has boosted the search for enhanced strategies. In this context, nanoparticles can be used as active PS because of their diverse design and increased penetration capacity within biofilms. Different nanoparticle-based PS strategies may be classified, as shown in Figure 5[61]. Nanoparticle-based PS present many advantages over free photosensitizing molecules. As pointed out by the growing literature [62], the conjugation of nanoparticles with PS significantly improves aPDT effects; this theme is addressed in this review. The most remarkable strategies where nanotechnology is applied to PS are discussed here. Mainly, the use of PS loaded in polymeric nanoparticles, nanoparticles as an active PS, PS in nanoemulsions, quantum dots and nanodiamond roles, and magnetic nanoparticles conjugated with PS are summarized in Box 2.