Pulmonary Drug Delivery in the Era of Nanomedicine: From Biological Barriers to Artificial Intelligence-Driven Optimization

Pulmonary drug delivery has become a vital route for both local and systemic treatments because of the unique structure and function of the respiratory system. Unlike oral and injectable dosage forms, inhalation offers a non-invasive, direct route to deliver medicines to the lungs, bypassing gastric degradation and first-pass hepatic metabolism. Common forms such as aerosols, solutions, suspensions, and dry powders are frequently used to treat respiratory diseases like asthma and chronic obstructive pulmonary disease (COPD). However, their effectiveness is often limited by physiological and biopharmaceutical barriers, such as mucociliary clearance, enzymatic degradation, and nonspecific deposition, which reduce drug retention and bioavailability. These issues are especially critical for poorly soluble or sensitive molecules, leading to lower drug concentrations at the target site and necessitating frequent dosing. To address these challenges, advanced nanoparticle-based delivery systems are being developed to improve drug stability, targeting, and controlled release within the lungs. At the same time, computational methods, including deposition modeling, physiologically based pharmacokinetic (PBPK) simulations, and AI-driven optimization, are increasingly used in formulation development to predict in vivo performance and boost translational success. This review covers the physiological and biological barriers to pulmonary drug delivery, explores major inhalation routes and dosage forms, and discusses new therapeutic strategies and nanoparticle platforms. It also highlights the growing role of in silico modeling and AI in accelerating the design and optimization of pulmonary treatments, while addressing current challenges, limitations, and regulatory issues in translating pulmonary nanomedicine into clinical practice.