**4. Nanotechnology and future perspectives for aPDT**

Antimicrobial Photodynamic Therapy is one of the main option that have been investigated against resistant bacteria. However, even with the use of some photosensitizers in the clinic, especially for tumor treatment and already approved by the FDA, some restrictions of these molecules, such as low solubility, little tissue penetration, low specificity and little accumulation in the target cells are some of the characteristics that hinders the greater use of this technique as the gold standard in various diseases [62] Nanotechnologies is one possibility to increase the efficacy of molecules with poor pharmacokinetics and pharmacodynamics properties, including PS [63].

Drug delivery is, therefore, one of the most challenges for aPDT [64]. For this reason, nanotechnology has been used in PDT as a possibility to increase its effect. Nano-systems can be stable (even under light), present good optical properties and high penetration in the tissue, as the skin (for topical application), have more specificity (with surface functionalization) and be more efficient in ROS production [62]. Nanomaterials can be used as PS itself or to load the PS (as carrier), opening several possibilities to conjugate nanotechnology with aPDT.

The nanoparticles used as drug carrier present some advantages in relation to traditional molecules, such as the transport in the blood circulation of hydrophobic substances, the incorporation of some antigen given them desired properties, the facility to enter in the target and yet, it is possible to control drug delivery [64]. Thus, several types of nanoparticles, with different sizes, shapes and functions, have been synthetized in the last years, including for aPDT [65]. They are classified according to their material: inorganic (as metal nanoparticles), organic (as liposomes) and nanocomposites, organic or inorganic [66].

Some nanomaterials have been explored under irradiation, showing photodynamic effect and have been applied in different tests. Gold and Silver nanoparticles, nanomaterials based in silica and silicon, quantum-dots, carbon-based materials and nanoparticles from organic molecules are examples of the materials already used in photodynamic therapy and its multimodal conjugation treatments in several application [62].

The nanosystems also enable the delivery of PS with desirable optical characteristics, such as the use of absorption by two photons or upconversion nanoparticles and can result in high penetration into the tissue. Thus, they can be activated from X-ray to infrared, reaching regions of the body that previously were not possible with traditional PDT. This prospect of applying nano PDT can make this technique extremely useful in the context of respiratory diseases, especially due to the current concern about infections caused by resistant bacteria, the pandemic of the coronavirus, or the next outbreaks that are yet to come [64].

However, it is still necessary to overcome the barrier between *in vitro* and *in vivo* studies to reach nanotechnology's clinical applications. Viral, fungal and bacterial infections characterize a global public health problem and, with the coronavirus pandemic, humanity saw the urgency to invest in new therapeutic possibilities, especially because new pandemics have been predicted. The advent of nanotechnology has helped to provide quick answers to urgent problems [63]. The scientific and clinical community's joint efforts and their integration into industry are needed to respond quickly to respiratory diseases [67].

APDT is increasingly becoming a viable option for upper and lower airway infections and nanosystems can help to break traditional PDT barriers. The search for highly efficient PS has been one of the main research lines when it comes to improving PDT. Many molecules synthesis methods have been explored, as well as the synthesis of nanoparticles, but they are usually complicated and, especially with nanoparticles, are difficult to apply for large-scale production. Thus, simpler synthesis methods with functionalization of these nanometric systems have been gaining relevance in the scientific community, since it is one of the challenges for the clinical implementation of nano-PDT [68]. It is also necessary to understand the parameters beyond the laboratory, such as dose, irradiation and clinical efficacy [69].
