Respiratory infections caused by coronaviruses (CoVs) have become a major public health concern in the past two decades as revealed by the emergence of SARS-CoV in 2002, MERS-CoV in 2012, and SARS-CoV-2 in 2019. The most severe clinical phenotypes commonly arise from exacerbation of immune response following the infection of alveolar epithelial cells localized at the pulmonary blood-air barrier. Preclinical rodent models do not adequately represent the essential genetic properties of the barrier, thus necessitating the use of humanized transgenic models. However, existing monolayer cell culture models have so far been unable to mimic the complex lung microenvironment. In this respect, air-liquid interface models, tissue engineered models, and organ-on-a-chip systems, which aim to better imitate the infection site microenvironment and microphysiology, are being developed to replace the commonly used monolayer cell culture models, and their use is becoming more widespread every day. On the contrary, studies on the development of nanoparticles (NPs) that mimic respiratory viruses, and those NPs used in therapy are progressing rapidly. The first part of this review describes in vitro models that mimic the blood-air barrier, the tissue interface that plays a central role in COVID-19 progression. In the second part of the review, NPs mimicking the virus and/or designed to carry therapeutic agents are explained and exemplified.