Precision nanomedicine for pulmonary diseases: from molecular targeting to clinical translation

The pulmonary system is a vital interface between the body and the external environment, making it highly vulnerable to environmental, infectious, and genetic insults. Precision nanomedicine offers a promising strategy to overcome the limitations of conventional gene and drug therapies, including safety concerns associated with viral vectors, instability of therapeutic agents, suboptimal cellular internalization, and a critical lack of tissue- and cell-specific targeting. Nanoparticle-based delivery platforms address these challenges by enhancing therapeutic stability and bioavailability, enabling controlled release, facilitating cellular uptake and endosomal escape, and achieving targeted delivery to specific lung compartments. While recent literature often focuses on specific nanoparticle types or isolated pathologies, this work provides a comprehensive overview of the current state of respiratory nanomedicine, bridging fundamental nanoparticle bioengineering with a wide range of pulmonary pathologies and the obstacles to clinical translation. We discuss the key physicochemical properties of nanoparticles for pulmonary biomedical applications, along with advanced design strategies for targeted delivery. Given the unique architecture and physiology of the lung, we compare the advantages and limitations of pulmonary versus systemic administration routes, emphasizing context-specific delivery strategies. Nanoparticle design and therapeutic applications are explored across a broad spectrum of diseases, including pulmonary fibrosis, chronic obstructive pulmonary disease, infections, pulmonary vascular disease, cystic fibrosis, asthma, lung cancers, and neonatal pulmonary disorders. Finally, we evaluate the current status of clinical trials, highlighting translational challenges such as biological barriers, long-term safety, and manufacturing. Future perspectives and interdisciplinary strategies are proposed to advance the clinical translation of nanocarriers for respiratory diseases.