Refractory pulmonary diseases, including chronic obstructive pulmonary disease (COPD) and tuberculosis (TB), pose a critical global health challenge due to the limitations of conventional therapies in advanced stages, such as poor drug penetration, systemic side effects, and inability to eradicate pathogens in protected microenvironments. While the lung's complex structure is essential for respiratory function, it also facilitates persistent damage from environmental and infectious agents. Nanomedicine provides a transformative approach by utilizing customizable carriers (e.g., ligand-gated targeting, stimuli-responsive payload release) to bypass physiological barriers through both passive mechanisms such as enhanced vascular permeability and active-targeting. Such platforms achieve hierarchical drug deposition-from organ-level accumulation to pneumonocyte-targeting-thereby addressing the spatial heterogeneity of therapy-resistant lesions. Besides, A unique advantage of nanomedicine lies in its intrinsic interactions with lung immune cells (e.g., macrophages), allowing dual-functional systems that not only deliver therapeutics to disease sites but also modulate local immune responses-such as reducing inflammation in COPD or enhancing bacterial clearance in TB. This targeted approach improves treatment efficacy while minimizing systemic toxicity. Furthermore, nanomedicine ensures the stability of encapsulated drugs, particularly nucleic acid therapeutics (siRNA, mRNA), which are crucial for treating genetic defect-related pulmonary diseases. Building on the relationship between malignant pulmonary conditions and lung cells, this review summarizes nanoplatform-based strategies for precise targeting and examines ongoing clinical trials. By bridging the gap between preclinical research and clinical application, this review aims to guide the development of novel therapeutic approaches and accelerate the clinical translation of nanomedicines for refractory pulmonary diseases.
