Starting from December 2019 in China, a novel virus of the Coronaviridae family, named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is spreading worldwide. SARS-CoV-2 infections range from asymptomatic to mild symptoms, up to severe acute respiratory distress syndrome (ARDS) and death. The development of new 3D models that mimic healthy and pathological lung tissue to understand the novel SARS-CoV-2 mechanisms of infection better and spreading of the virus is of paramount importance. Similarly, the identification of natural compounds able to act as antiviral drugs that can inhibit SARS-CoV-2 infection and/or replication and the development of new platform for controlled and localize delivery of therapeutic drugs would represent a powerful step to enhance the response to a possible second wave of the pandemic virus. In this project, we will try to generate a 3D model of healthy and pathological lung tissue and utilize it for experimental in vitro CoV infection models, with the low-pathogenic CoV OC43, 229E, and NL63, to understand better virus mechanism of action and spreading in a physiological environment. We will evaluate the use of candidate natural compounds such as glycyrrhizin for its ability to inhibit viral growth or decrease viral replication, in both 2D and 3D cell culture of infected A549 permissive cell line. We will then evaluate the use of functionalized silica and zinc nanowires for their ability to be used as a platform for controlled and localized drug delivery and assess the efficacy, function, and entry efficiency of the released drug in the 3D infected lung tissue model.