Inhaled Targeted Nano-Drug Delivery Systems for COPD: Precision Solutions to Clinical Barriers

Abstract: Chronic Obstructive Pulmonary Disease (COPD) is the third leading cause of death worldwide, with current pharmacotherapy constrained by low pulmonary drug deposition, pathological barriers, treatment resistance, and poor patient adherence. Nano-drug delivery systems (NDDS) offer a transformative strategy to overcome these obstacles. This review adopts a distinctive "clinically-driven” perspective, systematically exploring the structural design strategies of targeted inhaled NDDS tailored to each specific therapeutic bottleneck. We analyze a hierarchical progression of strategies—from the "nano-in-micro” approach to enhance pulmonary deposition post-inhalation, through diverse surface modification techniques to improve mucus penetration and cellular targeting, to intelligent stimuli-responsive systems enabling site-specific drug release. These design strategies are not applied in isolation but function synergistically, endowing NDDS with customized functionalities—including sustained lung retention, anti-inflammatory, antioxidant, anti-infective, or resistance-reversing effects—according to distinct therapeutic needs, enhancing local efficacy while reducing systemic side effects. Furthermore, we critically assess the current landscape of clinical trials for NDDS in COPD, dissecting key translational barriers such as preclinical model limitations, patient heterogeneity, and regulatory hurdles. Finally, we integrate and discuss emerging frontiers including artificial intelligence-guided design and multi-omics patient stratification, offering a forward-looking roadmap for the development of precision nanotherapeutics poised for clinical adoption. Keywords: chronic obstructive pulmonary disease, nano-drug delivery systems, clinical treatment, targeted drug delivery, clinical translation