Targeting Multiple Pathophysiological Axes in COPD: Nanomaterial Advances.

Chronic obstructive pulmonary disease (COPD), a leading global cause of mortality and morbidity, imposes substantial socioeconomic burdens due to its progressive nature and limited therapeutic efficacy. Current strategies face dual challenges: suboptimal pulmonary bioavailability of pharmacologic agents and systemic toxicity from non-targeted drug distribution. To address these limitations, this review establishes a mechanistic framework through the first systematic identification of COPD-specific nano-intervention targets, organized around four core pathophysiological axes: (1) dysregulated inflammatory cascades, (2) redox imbalance mechanisms, (3) protease-antiprotease homeostasis disruption, and (4) progressive airway remodeling. We critically evaluate respiratory-adaptive nanocarrier systems, including polymer nanoparticles (PLGA-PEG) with 6.5-fold enhanced Neutrophil targeting efficiency (*p* < 0.001) and lipid nanoparticles (LNPs) achieving >90% siRNA-mediated inflammatory gene suppression. Despite advancements, clinical translation remains hindered by technical limitations in nanoparticle engineering, chronic pulmonary biocompatibility risks (eg, silica nanoparticles elevating TGF-β by 1.8-fold, *p* < 0.05), and stringent regulatory requirements. Future research must prioritize intelligent stimulus-responsive platforms for inflammation-triggered drug release, multidisease targeting nanotechnologies, and AI-driven patient-specific formulations. By integrating mechanistic insights with translational strategies, this work provides a roadmap to advance nano-interventions toward precision therapeutics for COPD.