Pulmonary administration of nanomedicines, including viral vaccines, offers a direct, noninvasive route for both systemic delivery and lung-targeted therapy. However, natural lung defense mechanisms often lead to rapid clearance or degradation, limiting clinical translation. This challenge contrasts with the rising burden of lung diseases and emerging infections, highlighting the need for optimized pulmonary nanomedicines. We employ bottom-up synthetic protocols to develop multifunctional nanoparticles for imaging, therapy and the study of nano-biointeractions with the lung environment. Using multiscale models, we study mucus penetration, the composition of the lung surfactant corona and biodistribution in the lungs. Our findings show how molecular imaging provides insights into lung retention, penetration, and cellular uptake. We present multifunctional nanoparticles capable of drug encapsulation and contrast agent labeling, enabling multi-scale characterization of nano-bio interactions. Finally, we show how different surface coatings influence lung retention.