Targeting Multiple Pathophysiological Axes in COPD: Nanomaterial Advances

Qianyue Zhang,1,* Shuanglan Xu,2,* Chunyan Yang,3,* Xiaolan Wang,1 Ting Liu,1 Xinting Zhang,2 Chongchang Qu,2 Jiawang Wu,1 Jiao Yang,4 Xiqian Xing2 1Kunming Medical University, Kunming, Yunnan, 650500, People’s Republic of China; 2Department of Pulmonary and Critical Care Medicine, The Affiliated Hospital of Yunnan University, Key Laboratory of Respiratory Disease Research of Department of Education of Yunnan Province, Kunming, Yunnan, 650021, People’s Republic of China; 3Pulmonary and Critical Care Medicine, The Third Affiliated Hospital of Yunnan University of Traditional Chinese Medicine (Kunming Hospital of Traditional Chinese Medicine), Kunming, Yunnan, 650500, People’s Republic of China; 4Department of Pulmonary and Critical Care Medicine, First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, 650032, People’s Republic of China*These authors contributed equally to this workCorrespondence: Xiqian Xing, Department of Pulmonary and Critical Care Medicine, The Affiliated Hospital of Yunnan University, Key Laboratory of Respiratory Disease Research of Department of Education of Yunnan Province, Kunming, Yunnan, 650021, People’s Republic of China, Email [email protected] Jiao Yang, Department of Pulmonary and Critical Care Medicine, First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, 650032, People’s Republic of China, Email [email protected]: 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.Keywords: COPD, nanomaterial, drug delivery, targeted therapy, nanocarriers