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.

Introduction

Chronic Obstructive Pulmonary Disease (COPD) is a common, dynamic, heterogeneous lung condition characterized by persistent airflow limitation.¹ As the third leading cause of death worldwide, COPD resulted in approximately 3.4 million deaths in 2023, with a prevalence rate of nearly 10.3% among individuals aged 40 and above (approximately 480 million patients).^2–4 The pathophysiological mechanisms of COPD are complex, involving multiple factors such as chronic airway inflammation, oxidative stress imbalance, and epithelial–mesenchymal niche dysfunction, which collectively drive the disruption of the pulmonary microenvironment, progressively leading to aberrant structural remodeling and tissue destruction.^5–7 However, current inhaled drugs are not only hampered by the above mentioned pathological microenvironment that impairs drug deposition and penetration, but also have inherent drawbacks such as systemic side effects and an inability to reverse disease progression.^8–12 Coupled with issues of treatment resistance and poor adherence at the patient level, these disease–drug–patient factors intertwine to severely restrict the overall therapeutic efficacy of COPD.^13–16

Targeted nano-drug delivery systems (NDDS), as an emerging drug delivery platform, offer innovative solutions to overcome these clinical bottlenecks by leveraging their small size effect, high specific surface area, and surface functionalization capabilities.^8,17–20 Currently, several reviews have summarized the application of NDDS in COPD; however, most adopt a “nanocarrier centric” approach, focusing on the physicochemical properties and formulation engineering of various nanoplatforms, or concentrating on specific pathological axes or particular cell types.^6,21 This review innovatively adopts a “clinically ‑driven” perspective, beginning with a delineation of the key obstacles in COPD treatment, and accordingly analyzing the targeted design strategies and application progress of NDDS that address them. On this basis, we further provide an in-depth evaluation of the current status of clinical studies on pulmonary nanomedicines and systematically discuss critical translational barriers (eg, preclinical models, patient heterogeneity, quality control, and regulatory approval). Finally, we outline how emerging approaches such as artificial intelligence (AI) empowerment and multi omics patient stratification can facilitate the development of precision nanotherapeutics for COPD, thereby offering a practical roadmap to bridge nanomaterial innovation and clinical practice.

Current Status and Challenges of Clinical COPD Treatment

Limitations in Targeting Efficiency of Inhaled Drugs and Systemic Side Effects

Current pharmacological management of COPD follows the Global Initiative for Chronic Obstructive Lung Disease (GOLD) strategy, which emphasizes individualized treatment based on symptom burden and exacerbation risk.³ Inhaled bronchodilators—primarily long-acting beta₂-agonists (LABAs) and long-acting muscarinic antagonists (LAMAs)—remain the cornerstone of therapy. For patients with persistent symptoms or high exacerbation risk, treatment is escalated to LABA/LAMA combination or triple therapy (with inhaled corticosteroids, ICS).^3,22 Despite the theoretical advantage of direct pulmonary delivery, the therapeutic efficacy of inhaled drugs is severely limited by multiple factors. First, the pulmonary deposition fractions of commonly used inhaled formulations (eg, Budesonide/Formoterol, Indacaterol/Glycopyrronium, etc) is affected by the inhaler device type, patient handling technique, and formulation-specific physicochemical constraints.^23–27 Second, drug particles must traverse the complex and narrow branched airways of COPD patients and effectively penetrate the thickened mucus barrier in order to reach their target sites and exert therapeutic effects;^28–30 the restrictive effect of these physiological barriers is further modulated by disease severity. For example, a quantitative study based on gamma scintigraphy demonstrated that the total lung deposition of a triple therapy formulation reached 35.2% of the emitted dose in patients with mild-to-moderate COPD, whereas this proportion decreased to 28.7% in patients with severe/very severe disease.^31,32

Furthermore, even with inhalation administration, systemic absorption occurs—either via pulmonary capillaries or through oropharyngeal swallowing and subsequent gastrointestinal uptake—leading to definite systemic adverse effects.^3,33,34 These adverse effects are not merely theoretical concerns but are frequently observed in clinical practice. Taking the triple therapy of budesonide/glycopyrrolate/formoterol as an example, the incidence of adverse events reached 23.9% in patients during the 12‑week follow‑up period.³⁵ A meta‑analysis encompassing 91,021 patients confirmed that dual LAMA/LABA therapy and triple LABA/LAMA/ICS therapy significantly increased the risk of major adverse cardiovascular events compared with ICS/LABA.³⁶ The long‑term risks are even more serious—ICS use for more than one year was associated with a 41% increase in the risk of pneumonia.³⁷ Table 1 summarizes the systemic adverse reactions of commonly used inhaled drugs, highlighting the ongoing clinical challenge of balancing efficacy and safety.

Table 1.

Systemic Adverse Reactions of Common Inhaled Drugs in COPD

Drug Class	Common Systemic Adverse Reactions	Mechanism
LABA	Tremor, tachycardia, headache, hypokalemia	Result from activation of systemic beta2-adrenergic receptors after drug absorption
LAMA	Dry mouth, cough, constipation, urinary retention, blurred vision	Result from antagonism of systemic muscarinic receptors
ICS	Oral candidiasis, dysphonia, skin bruising; long-term high-dose use may increase risk of pneumonia, osteoporosis, adrenal suppression	Local immunosuppression leading to opportunistic infections; systemic absorption causing steroid effects
Phosphodiesterase-4 Inhibitors	Diarrhea, nausea, weight loss, headache, sleep disorders	Exert anti-inflammatory effects by inhibiting systemic phosphodiesterase-4 enzymes; gastrointestinal side effects prominent

Abbreviations: LABA, Long-Acting Beta₂-Agonist; LAMA, Long-Acting Muscarinic Antagonist; ICS, Inhaled Corticosteroids.

Multiple Biological Barriers in the COPD Pathological Microenvironment

The COPD lung presents a complex, dynamically remodeled barrier network.^38,39 Starting from the macrostructure, persistent airway inflammation induces fibrotic thickening of the airway wall, luminal narrowing, and alveolar destruction, which disrupt normal aerosol flow and distribution, thereby limiting drug access to distal lesions.⁴⁰ Concurrently, damage to pulmonary microvascular endothelial cells compromises the integrity of the blood-air barrier, leading to non-targeted drug loss.⁴¹ At the chemical and physical level, changes in the airway mucus barrier are particularly critical. Chemically, clinical cohort data have demonstrated that the mucus composition in COPD patients undergoes significant alterations, characterized by markedly elevated concentrations of the gel‑forming mucin MUC5AC, along with increased levels of extracellular DNA.^42,43 Physically, mucus hypersecretion coupled with increased solid content substantially enhances the viscoelasticity and rigidity of the mucus gel.^44,45 These physicochemical changes result in a marked reduction of the gel network pore size; in severe COPD patients, the effective pore size can drop below the 100‑nanometer threshold, severely hindering the penetration of inhaled drug carriers through the mucus barrier.⁴⁶ Secondly, smoking and COPD can lead to a global downregulation of genes associated with tight junctions in epithelial cells, compromising airway epithelial barrier function and causing abnormal drug diffusion.^47,48 Importantly, epithelial cell injury induces epithelial-mesenchymal transition (EMT) and aberrantly activates mesenchymal cells, thereby promoting cellular injury, peribronchiolar fibrosis, alveolar destruction and impaired tissue repair.^7,49 Consequently, this dysfunction of the epithelial-mesenchymal niche microenvironment drives extracellular matrix barrier remodeling, culminating in a denser fibrotic network that further impedes drug diffusion into the affected regions.^50–52 Alveolar macrophages, key cells of the immune barrier, become dysfunctional in COPD, potentially exhibiting phagocytic defects, yet their clearance activity towards foreign substances persists, significantly affecting the effective retention time of drugs in the lungs.⁵³ These dynamic barrier changes collectively constitute a complex defensive network that greatly limits drug penetration, distribution, and retention in the COPD lung – a core challenge that must be overcome for effective targeted therapy.

Bacterial Biofilms and Chronic Infection

COPD patients often experience bacterial colonization and chronic infection due to altered respiratory tract structure and impaired immune function, closely linked to recurrent acute exacerbations and disease progression.⁵⁴ Common colonizing pathogens include Haemophilus influenzae, Pseudomonas aeruginosa, and Streptococcus pneumoniae.^55–57 These colonizing bacteria can form biofilms in the patient’s airways – structured communities encased in a self-produced matrix of extracellular polymeric substances (EPS).^58,59 This EPS matrix not only constitutes a physical diffusion barrier but also carries a negative charge that can electrostatically adsorb and neutralize positively charged antibiotics, significantly hindering drug penetration.^12,60 Consequently, the resistance of bacteria within biofilms can be up to 1000 times higher than that of planktonic bacteria.^12,61–63 Biofilms continuously stimulate tracheal mucus secretion, and the thickened mucus further restricts antibiotic penetration, making the encased bacteria even more persistent.^64–66 This formidable composite barrier greatly impedes drug penetration, making it difficult for traditional inhaled or systemic antimicrobial regimens to effectively clear pathogens, leading to persistent infection, ongoing inflammation, and accelerated decline in lung function.^12,28

Disease Heterogeneity and Treatment Resistance

The high heterogeneity of COPD and the prevalent treatment resistance are core challenges for effective clinical management.^67–69 This heterogeneity stems from complex genetic backgrounds among patients and is also reflected in the significantly different responses to medication across various clinical phenotypes (eg, frequent exacerbator, emphysema-predominant, asthma-COPD overlap).^70,71 Treatment resistance is particularly prominent for glucocorticoids.^72,73 For example, a post-hoc analysis of the FLAME trial confirmed that current smokers with COPD had significantly reduced responses to ICS‑containing regimens.⁶⁹ A key mechanism is reduced activity and expression of histone deacetylase 2 (HDAC2), which leads to persistent activation of inflammatory genes and diminished GC efficacy.⁷⁴ Persistent oxidative stress in COPD lungs impairs HDAC2 activity, amplifying inflammation and inducing GC resistance.^74,75 This core mechanism is closely related to the patient’s specific pathological microenvironment.^76–78 For instance, recent studies also show that long‑term smoking activates nuclear factor erythroid 2-related factor 2 (NRF)-related signaling in neutrophils, inducing ferroptosis resistance and abnormal neutrophil survival.⁷⁶ These cells release neutrophil extracellular traps, driving a pro-inflammatory microenvironment that downregulates glucocorticoid receptor‑α and HDAC2, thereby weakening GC action.⁷⁶ This resistance mechanism is driven by specific immune cells, and multiple studies have confirmed that patients with COPD exhibit quantifiable differences in immune cell phenotypes and functions.^73,76,79,80 These diverse differences may contribute to varying degrees of treatment responsiveness among patients to the same therapeutic regimen, which also explains why a “one-size-fits-all” dosing strategy fails in some cases.^72,81,82

The Real-World Challenge of Poor Patient Adherence

Poor medication adherence in COPD patients is also a critical factor leading to suboptimal treatment outcomes and failure in disease management. Imran Sulaiman et al, using electronic audio recording devices (INCA) to objectively monitor elderly COPD patients, found that the mean actual adherence rate was only 22.6%, with only about 6% of patients achieving adherence levels above 80%.⁸³ Factors affecting medication adherence in COPD are multifaceted. First, COPD prevalence is positively correlated with age, and elderly patients often present with reduced manual dexterity, cognitive decline, and comorbidity burdens, all of which substantially compromise adherence.^84–88 Second, disease perception bias (eg, underestimation of long‑term maintenance benefit) interacts with treatment regimen complexity (often requiring multiple daily doses and combined devices), prompting patients to self‑adjust or discontinue therapy once symptoms improve.^89–91 Moreover, unlike most chronic conditions such as hypertension and diabetes that rely primarily on oral medications, the efficacy of inhalation therapy is closely tied to both the inhaler device type and patient handling technique.^92–94 These factors render adherence in COPD far more than a mere “attitudinal” issue, but rather a multidimensional challenge involving physical function, cognition, and technical skills.⁸⁹ This widespread non-adherence directly undermines the potential clinical benefits of pharmacological treatment and is significantly associated with adverse health outcomes such as increased risk of exacerbations, higher hospitalization rates, and elevated all-cause mortality.^83,95 It is also a major contributor to high healthcare costs. Therefore, identifying and addressing barriers to medication use in COPD patients, and developing intelligent drug delivery systems that can extend dosing intervals and simplify operational procedures, are crucial for improving patients’ long-term prognosis.

Core Advantages and Design Strategies of NDDS

NDDS generally refers to technologies that utilize biocompatible nanoparticles (typically in the size range of 1–1000 nanometers) as carriers to load therapeutic drugs through approaches including encapsulation, adsorption, and chemical conjugation, enabling precise delivery to specific target sites and controlled release.^96–98 The core design principle leverages the unique physicochemical properties of nanoscale materials, such as high specific surface area, modifiable surface functionality, and size compatibility with biological systems, to overcome the inherent limitations of conventional drug administration.^99–101 For COPD, systemic NDDS suffer from reticuloendothelial clearance and poor lung bioavailability, whereas inhaled NDDS bypass these barriers for direct airway delivery.¹⁰² These systems can effectively protect drugs from premature degradation or clearance and significantly enhance drug accumulation in diseased lung tissue through passive targeting (eg, enhanced permeability and retention effect) or active targeting (eg, surface modification with specific ligands) strategies.^103,104 Concurrently, by responding to the lesion microenvironment (eg, pH, enzymes, redox state) or external stimuli (eg, light, magnetism), they enable intelligent, controlled drug release, thereby improving drug bioavailability and efficacy while minimizing systemic exposure and related toxic side effects.^105–108

Nanocarrier platforms encompass diverse types, each endowed with distinct physicochemical properties and biological functions. By systematically tuning key design parameters—such as particle size, surface charge, and stimulus‑response thresholds—pulmonary deposition efficiency, mucus penetration capability, cellular uptake pathways, and drug release kinetics can be precisely optimized.^109–111 This tunability enables the rational matching of carrier characteristics to the complex pathophysiological microenvironment of COPD. Table 2 provides a comparative overview of major nanocarrier classes, summarizing their core advantages and the formulation parameters that critically govern pulmonary delivery performance. Collectively, despite their structural diversity, these systems share a unified design philosophy: harnessing nanoparticle physicochemical properties to tackle specific COPD clinical challenges, thereby advancing therapeutic optimization and clinical translation.

Table 2.

Overview of Common Nano-Drug Delivery System Carriers

Carrier Type	Common Classifications	Core Advantages	Key Formulation Parameters for Pulmonary Delivery	COPD Adaptability Assessment	References
Lipid-Based Nanoparticles	Liposomes	Can load hydrophilic, hydrophobic, and lipophilic drugs; surface modifiable for extended circulation; high biocompatibility	Lipid composition, PEG density, cholesterol content, surface charge	High—biocompatible, mucus penetration, clinically proven	[17,109,112,113]
	Lipid Nanoparticles	Suitable for nucleic acid delivery; ionizable lipids facilitate endosomal escape	Ionizable lipid structure, N/P ratio, PEG-lipid content, particle size	High—can target lung tissue, good for gene therapy	[114–116]
Polymer-Based Nanoparticles	PLGA Nanoparticles	Biodegradable, FDA-approved, tunable degradation kinetics	Molecular weight, lactic: glycolic ratio, end-group chemistry, surface charge	Moderate-to-High—proven biosafety, immunoproteasome targeting	[117–120]
	Polymeric Micelles	Hydrophobic core solubilizes poorly soluble drugs; enhanced permeability and retention effect	Block copolymer composition, critical micelle concentration, PEG length	Moderate—passive targeting, kinetic instability limits pulmonary retention	[121–124]
	Dendrimers	Precise, highly controllable structure	Surface functional groups, PEGylation	Moderate—potential cytotoxicity, complex synthesis	[125–128]
Inorganic Nanoparticles	Gold Nanoparticles	Easily functionalized surface; unique optical properties	Core size, shape (sphere/rod), surface coating ligand	Low—non-biodegradable, long-term toxicity concerns	[129–131]
Protein Nanoparticles	Protein/Peptide-Based Nanoparticles	Naturally biocompatible; low immunogenicity	Protein source, crosslinking degree, surface charge	Moderate-to-High—stability challenges under active investigation	[132–134]
Composite Nanosystems	Biomimetic Nanoparticles	Natural targeting ability, homing effect	Membrane source, coating integrity, preservation of surface proteins	High—cell-membrane coating confers stealth and targeting	[111,135,136]
	Stimuli-Responsive Nanoparticles	High spatial controllability; rapid and complete drug release	Response threshold (pH/enzyme/redox), sensitivity range	High—matches COPD microenvironment heterogeneity, precise drug release	[137–139]
Small Molecule Self-Assembling Nanosystems	Small Molecule Prodrug/Pure Drug Self-Assemblies, Co-assemblies	Extremely high drug loading; avoids carrier-related toxicity	Prodrug linker chemistry, critical assembly concentration, stability in lung fluid	Moderate—limited drug selection scope	[140–143]

Abbreviations: COPD, Chronic Obstructive Pulmonary Disease; FDA, Food and Drug Administration (USA); PEG, Polyethylene Glycol; PLGA, Poly(Lactic-co-Glycolic Acid).

Nano-Delivery Strategies Targeting Clinical Challenges

As illustrated in Figure 1, targeted NDDS offers systematic solutions to the clinical challenges of COPD through diverse design strategies. These strategies encompass carrier material selection, surface functionalization, and particle size modulation, with the goal of covering the entire therapeutic course—from prolonging drug action via sustained release to improving adherence, to sequentially overcoming airway biological barriers, to achieving targeted accumulation in lesions, and ultimately to eliciting therapeutic efficacy. The successful implementation of these strategies relies on precise control of nanoparticle parameters and a thorough understanding of the underlying disease pathology. Table 3 summarizes representative examples, illustrating how specific combinations of carrier materials, active ingredients, and physicochemical properties translate these concepts into practical formulations.

Figure 1.

Schematic diagram of the strategy for targeted NDDS to address the clinical treatment challenges of COPD. The left panel lists the clinical obstacles: (1) low pulmonary deposition (blue drug particles confined to large bronchi with limited access to small airways); (2) mucus barrier (dashed arrows: restricted penetration); (3) bacterial biofilm; (4) therapeutic resistance (drug locked); and (5) poor patient adherence (irregular dosing schedule). The middle panel presents the engineering approaches: surface engineering, ligand conjugation, multi‑drug loading, smart responsive release, size optimization, and sustained release. The right panel shows the corresponding therapeutic outcomes: (1) enhanced pulmonary deposition; (2) improved mucus penetration; (3) biofilm disruption; (4) resistance reversal (drug unlocked); and (5) simplified regimen to improve adherence. Arrows denote the transition from challenges to solutions.

Table 3.

Representative Nano-Drug Delivery Systems for Addressing Key Clinical Challenges in COPD

Therapeutic Strategy	Nanocarrier Type	Active Ingredient(s)	Physicochemical Properties	Functional Modifications	Outcome	Reference
Enhancing Pulmonary Deposition	Nanocomposite Microparticles (NCMPs)	miR-146a	Size: 244.8 ± 4.40 nm (initial NPs); 409.7 ± 10.05 nm (recovered)	15% DOTAP cationic lipid for miRNA adsorption	FPF 51.33%; preservation miR-146a bioactivity with IRAK1 and TRAF6 gene silencing	[144]
	Mannosylated lipid/polymer hybrid nanoparticles (Man‑LPHNPs)	Rapamycin	Size: ~128 nm (LPHNPs); 4.52 μm (microparticles, geometric diameter); Zeta potential: −13.8 mV	Mannose targeting (DSPE‑PEG2000‑Man); PEG2000 modification; DPPC lipid shell for lung biocompatibility	Retention of 74% intact drug after 24 h (vs 40% for free drug); active alveolar macrophage targeting	[106]
Enhancing Pulmonary Retention	PEGylated SLNs	Curcumin	Size: 78.5±2.6 nm (SLN); 3.93 μm (composite geometric); Zeta potential: negatively charged	PEG2000 modification	Prolongation of lung retention (6‑fold higher lung Cmax vs unmodified group; strong lung fluorescence signal at 12 h by in vivo imaging); low systemic exposure	[109]
Enhancing pulmonary targeting	PEGylated immuno‑conjugated PLGA nanoparticles	Ibuprofen	Size: 344.5 ± 35 nm; Zeta potential: negatively charged	PEG2000 modification; surface conjugation with NIMP‑R14 antibody	Neutrophil‑specific targeting; reduction of non‑specific distribution	[145]
	Neutrophil-mimicking nanoparticles	Levofloxacin	Size: ~122 nm; Zeta potential: −8.8 mV	Neutrophil membrane coating	Prolongation of lung retention (>36 h); enhancement of mucus penetration (from ~4 h to 30 min); active inflammatory cytokine neutralization	[111]
Penetrating Mucus Barrier	PEGylated Small Unilamellar Liposomes	Beclomethasone dipropionate	Size: 70 ± 10 nm; Zeta potential: −2.4 ± 0.3 mV	PEG2000-PE modification	Excellent mucus penetration (18.8% at 27 h in COPD sputum); good safety.	[146]
	DPPC‑coated PLGA lipid‑polymer hybrid nanoparticles	N‑acetylcysteine (NAC)+ all‑trans retinoic acid (ATRA)	Size: ~400 nm; Zeta potential: ~+1 mV	DPPC lipid coating; NAC loaded in lipid shell (fast release); ATRA encapsulated in PLGA core (sustained release)	Enhancement of mucus penetration (26.5‑fold higher vs NAC‑free control); sustained drug release (ATRA)	[117]
Eradicating Bacterial Biofilms	PEGylated chitosan nanospheres loaded with black phosphorus quantum dots	Amikacin	Size: ~200 nm; Zeta potential: +7.8±2.5 mV	PEG surface modification; chitosan positive charge (mucoadhesion), and BPQDs doping (promoting drug release)	Antibacterial rate >90%; effective disruption of biofilms; induction of bacterial membrane depolarization; rapid drug release (>70% Amikacin within 7 h)	[147]
	Polypeptide‑gated hollow mesoporous silica nanoparticles	Ceftazidime	Size: 123 nm; Zeta potential: −30 mV	pH‑responsive charge/conformation‑transformable polypeptide (surface modification)	Efficient biofilm penetration (depth >2.7 μm) and eradication; synergistic bactericidal activity (in vivo bacterial reduction ~98%); anti-inflammatory effects.	[12]
Redox/Inflammatory Microenvironment Modulation	Nanostructured Lipid Carriers	Magnolol	Size: 19.67±0.36 nm; Zeta potential: −5.18±0.69 mV	No targeting modification	Anti‑inflammatory and antioxidant effects via activation of Nrf2/HO‑1 pathway and inhibition of NF‑κB signaling	[115]
	Macrophage membrane‑biomimetic bimetallic manganese‑platinum nanozymes	Mn‑Pt bimetallic nanozymes	Size: 112.68 nm; Zeta potential: −30.4 mV	Macrophage membrane coating; DSPE‑PEG‑NH2 hydrophilic modification	Anti‑inflammation and antioxidant via inhibiting ROS‑PI3K‑AKT pathway; improvement of lung function	[148]
	Noninflammatory Lipid Nanoparticles	siRNA targeting MUC5AC	Size: 168.1±2.3 nm (N/P=3); Zeta potential: −1.99±0.44 mV	Ursolic acid incorporation (anti‑inflammatory); Low‑immunogenicity ionizable lipid; N/P ratio modulation	MUC5AC protein silencing efficiency 85%; reduction of immune cell infiltration; alleviation of inflammation; excellent biosafety	[149]
Promoting Tissue Repair	SS‑OP nanoparticles	Tamibarotene (Am80)	Size: 138 ± 2.85 nm; Zeta potential: −6.43 ± 2.87 mV	SS‑OP lipid (endosomal escape + glutathione‑responsive release); Apolipoprotein E adsorption (cellular uptake)	Nuclear‑targeted Am80 delivery (>70% release within 3 h under reducing conditions); alveolar regeneration	[150]
	SM102 lipid nanoparticles	Hepatocyte growth factor‑encoding mRNA	Size: 64–84 nm; Zeta potential: ~12–15 mV	SM102 LNP encapsulation (lung‑specific delivery)	Alveolar regeneration via WNT/β‑catenin activation (AKT‑GSK3β axis); promotion of alveolar epithelial cell proliferation and differentiation	[151]
Reversing Treatment Resistance	Lipid‑polymer nanoparticles	Mn‑porphyrin dimer (MnPD) and HDAC2‑encoding plasmid DNA	Size: ~123±31 nm; Zeta potential: +11 mV (N/P=8)	PLA core (MnPD encapsulation, ROS elimination) + DOTAP shell (gene delivery)	Synergistic elimination of ROS and upregulation of HDAC2; amelioration of glucocorticoid resistance	[152]
Improving Patient Adherence	Poly(malic acid)-budesonide nanoconjugates	Budesonide	Size: ~80–100 nm; Zeta potential: −51 to −66 mV	Self‑assembled poly(malic acid)-budesonide nanoconjugates	Sustained pulmonary retention (budesonide detected in alveolar cells up to 48 h post‑administration); low systemic exposure	[140]
	Myricetin‑loaded inhalable microspheres	Myricetin	Size: 7.72±0.23 μm; Zeta potential: −21.37±0.85 mV	Ionotropic gelation crosslinking (gellan gum + sodium alginate + Ca2⁺)	Sustained drug release over 12 h; excellent stability over 6 months under both accelerated and real‑time storage conditions	[153]

Abbreviations: Am80, Tamibarotene; ATRA, All-Trans Retinoic Acid; BDP, Beclomethasone Dipropionate; BPQDs, Black Phosphorus Quantum Dots; COPD, Chronic Obstructive Pulmonary Disease; DOTAP, 1,2-Dioleoyl-3-trimethylammonium-propane; DPPC, Dipalmitoylphosphatidylcholine; DSPE, Distearoylphosphatidylethanolamine; FPF, Fine Particle Fraction; HDAC2, Histone Deacetylase 2; IRAK1, Interleukin-1 Receptor-Associated Kinase 1; LPHNPs, Lipid/Polymer Hybrid Nanoparticles; Man, Mannose; MMAD, Mass Median Aerodynamic Diameter; Mn‑Pt, Manganese‑Platinum; MUC5AC, Mucin 5AC; NAC, N‑Acetylcysteine; NCMPs, Nanocomposite Microparticles; NF‑κB, Nuclear Factor Kappa B; N/P, Nitrogen‑to‑Phosphorus ratio; Nrf2, Nuclear Factor Erythroid 2‑Related Factor 2; PEG, Polyethylene Glycol; PLA, Poly(Lactic Acid); PLGA, Poly(Lactic‑co‑Glycolic Acid); PMA, Poly(Malic Acid); ROS, Reactive Oxygen Species; siRNA, Small Interfering RNA; SLNs, Solid Lipid Nanoparticles; SS‑OP, SS‑cleavable proton‑activated lipid‑like material; TNF, Tumor Necrosis Factor; TRAF6, TNF Receptor‑Associated Factor 6.

Enhancing Pulmonary Deposition Efficiency and Reducing Systemic Exposure

In patients with COPD, airway pathological obstruction predisposes the bifurcations to airflow disturbances and elevated local flow velocities, significantly increasing the collision frequency and deposition propensity of nanoparticles onto the airway wall.^11,154 Systematic optimization of nanomedicine particle size, morphology, density, and surface properties through precise engineering approaches can preclinically improve targeted deposition efficiency in diseased lungs and overcome COPD-related airway structural abnormalities and fluid dynamic barriers.^11,155 For instance, to address the issue that nanoparticles (<1 μm) are prone to exhalation, a prevalent strategy is the “nano-in-micro” (NiM) approach, wherein inhalable micron-scale carriers encapsulate the nanoformulations for pulmonary delivery.^156,157 Structurally, this design cleverly combines the advantages of both: the internal nano-units ensure high specific surface area, solubility, and biological activity of the drug; the external micron-sized matrix (1–5 μm in diameter) provides suitable aerodynamic properties, enabling the particles to overcome the abnormal airflow resistance in COPD patients and deposit in the deep respiratory tract.^156,158

In practice, spray drying is a common technique for preparing NiM formulations, enabling precise control of particle size distribution and morphology via process parameters and formulation composition.^159–161 Beyond these aerodynamic and structural benefits, this technology also enables efficient loading of nucleic acid dry powders onto nanoparticles while protecting moisture-sensitive nucleic acid drugs from degradation during processing, thereby restoring their biological activity upon particle reconstitution.¹⁶² For instance, nanocomposite microparticles containing miR-146a, siRNA-loaded lipid nanoparticles (LNPs), and rapamycin-loaded polyethylene glycol (PEG)ylated nanoparticles embedded in mannitol microspheres have all been successfully formulated as dry powder inhalers, demonstrating good solubility, mucus penetration, and retained bioactivity in vitro.^114,144,157 Similarly, using fast-dissolving flower-like lactose as a carrier, curcumin-loaded PEGylated solid lipid nanoparticles (SLNs) were stably delivered to small airways in a mouse model, reducing systemic drug exposure.¹⁰⁹

Furthermore, by modulating particle crystallinity, morphology, and density, spray drying technology can further optimize the aerosolization characteristics and permeability of dry powders, with in vitro and in silico evidence suggesting the potential for efficient and predictable deposition of poorly soluble drugs in diseased COPD airways.^163,164 Beyond simple embedding, constructing core-shell structured hybrid microparticles can enhance functionality. For example, Craparo et al prepared core-shell lipid/polymer hybrid nanoparticles with excellent aerodynamic properties, and the mannosylated phospholipids in the shell enabled in vitro active targeting of macrophages.¹⁰⁶ In preclinical animal models, these diverse NiM strategies resolve the paradox where naked nanoparticles are easily exhaled or deposit in the upper airways, while micron-sized particles alone are poorly taken up by cells.^109,140 This staged delivery approach cleverly balances the requirements for macroscopic pulmonary deposition and microscopic cellular delivery.

Surface Modification for Enhanced Pulmonary Retention and Targeting

Upon inhalation, nanoparticles rapidly adsorb proteins, lipids, and mucins from pulmonary surfactants onto their surface, forming a biomolecular corona that critically governs mucus penetration, cellular uptake, immune recognition, and biodistribution.^165,166 This unique biological interface imposes higher demands on NDDS design, necessitating not only consideration of the intrinsic physicochemical properties of nanoparticles but also rational surface engineering to tailor them to the specific pathological microenvironment of COPD. PEGylation is the most widely applied foundational strategy. Grafting hydrophilic, flexible PEG chains onto the nanoparticle surface effectively imparts “stealth” properties, significantly reducing non-specific interactions with negatively charged lung mucus components and markedly decreasing recognition and phagocytosis by alveolar macrophages, thereby passively extending the drug’s duration of action at the target site.^{109,145–147,157,167} In specific applications, PEG2000 modification reduces aggregation of curcumin nanoparticles via steric hindrance, diminishes mucociliary clearance and macrophage phagocytosis in vitro, significantly increasing curcumin concentration and retention time in the lungs in mice.¹⁰⁹

To achieve active cellular targeting, researchers introduce specific ligands onto the nanoparticle surface. For instance, modifying lipid-polymer hybrid nanoparticles with mannose enables specific binding to mannose receptors highly expressed on macrophage surfaces, thereby initiating active, receptor-mediated endocytosis for precise intracellular delivery of anti-inflammatory drugs like roflumilast or immunosuppressants like rapamycin.^106,168 For neutrophils, which heavily infiltrate the airways of COPD patients, conjugating anti-neutrophil antibodies (eg, NIMP-R14) to PEGylated Poly(lactic-co-glycolic acid) (PLGA) nanoparticles creates a targeted system capable of actively recognizing and delivering drugs like ibuprofen to neutrophils via intranasal instillation.¹⁴⁵ This approach effectively controlled neutrophilic inflammation and reduced alveolar destruction in acute and chronic murine inflammation models.

Notably, biomolecular corona formation compromises the in vivo targeting efficiency of ligand-modified nanoparticles, which can be modulated via biomimetic camouflage.^169,170 Coating levofloxacin-loaded PLGA nanoparticles with neutrophil membranes yields biomimetic nanoparticles that retain source cell membrane proteins and functions. These nanoparticles can neutralize pro‑inflammatory cytokines, efficiently penetrate mucus layers, and mimic neutrophil chemotaxis to traverse the dense mucus barrier and deliver drugs to deep lesions.¹¹¹ Furthermore, Peng et al constructed hybrid membrane vesicles with dual targeting functions by fusing neutrophil membranes with E. coli membranes, used to encapsulate norfloxacin-loaded LNPs.¹⁷¹ This hybrid vesicle possesses both the neutrophil membrane’s ability to target inflamed vascular endothelium and the bacterial membrane components’ specific recognition and binding affinity for homologous Gram-negative bacteria. This dual targeting enables precise accumulation at the infection site, evasion of immune clearance, and effective penetration and eradication of bacterial biofilms in mouse models. Although primarily validated in infection models like acute bacterial pneumonia via intratracheal administration, this dual-targeting design precisely corresponds to the key characteristic of coexisting “inflammatory microenvironment” and “colonizing pathogens” in COPD airways. Although the above-mentioned studies do not explicitly address the biomolecular corona, and current research on biomolecular corona modulation in inhaled formulations for COPD remains exploratory, these progressive surface modification strategies—ranging from basic PEGylation to ligand-mediated active targeting and on to biomimetic membrane camouflage—lay a solid foundation for the development of next generation multifunctional targeted nanoformulations for COPD.

Nano-Design Strategies for Penetrating the Mucus Barrier

To overcome the dense mucus barrier in the airways of COPD patients, researchers have developed various nano-delivery strategies based on size control, surface engineering, and intelligent responsiveness. Firstly, reducing nanoparticle size to less than 200 nm facilitates passage through the limited pores of the mucin network. Simultaneously, imparting hydrophilic or neutrally charged surface properties minimizes electrostatic and hydrophobic interactions with negatively charged mucins. Common modification methods include surface hydrophilic modification (eg, PEGylation) and charge modulation.^{12,121,172,173} For instance, PEG2000 surface modification of liposomes delivering beclomethasone dipropionate demonstrated the strongest penetration capability and good biosafety in pathological mucus models derived from COPD patients.¹⁴⁶ Another innovative strategy involves using an external magnetic force to actively pull nano-therapeutics through the mucus barrier; for example, a magnetic field significantly enhanced the penetration efficiency of magnetic iron oxide-loaded SLNs through sputum from COPD outpatients.¹⁷⁴

To actively disrupt the mucus structure, Kumari et al conjugated mannitol onto a chondroitin sulfate A polymer and coated it onto nucleic acid nanocomplexes; in this functional coating, chondroitin sulfate A reduces the positive surface charge of the particles to minimize electrostatic adsorption with negatively charged mucin, while mannitol lowers mucus viscosity by disrupting mucin-mucin interactions or promoting water influx, thereby significantly enhancing the diffusion and penetration efficiency of the nanocomplexes in artificial mucus.¹⁷⁵ Recent research constructed dipalmitoylphosphatidylcholine -coated PLGA nanoparticles by encapsulating the clinically used mucolytic agent N-acetylcysteine in the lipid shell to penetrate the mucus barrier, while incorporating the anti-inflammatory drug all-trans retinoic acid in the PLGA core, resulting in a 26.5-fold increase in nanoparticle penetration efficiency through the mucus layer and demonstrating potent anti-inflammatory activity in a human lung-on-a-chip model.¹¹⁷

A more intelligent approach involves environmentally responsive “charge-reversal” systems. For example, Li et al used 2,3-dimethylmaleic anhydride (DA) to modify PEGylated nanoparticles (DA-AZI-NPs). In the physiological neutral pH environment of mucus, the surface is negatively charged, favoring reduced capture and efficient mucus layer penetration to reach the infection site. Upon reaching the acidic microenvironment of bacterial biofilms, the DA groups hydrolyze and detach, restoring a strongly positive surface charge conducive to subsequent drug release and bacterial killing.¹³⁷ Although this study was not conducted in COPD animal models, the established Pseudomonas aeruginosa chronic infection model is highly relevant to the common comorbidity of P. aeruginosa colonization and infection in COPD patients. Similarly, a drug delivery system combining PEGylated chitosan nanospheres with black phosphorus quantum dots (BPQDs) features a PEG shell providing hydrophilicity and “stealth” properties, while BPQDs degrade in vivo creating an acidic microenvironment. This accelerates nanosphere disassembly and promotes antibiotic release, a synergistic action that significantly enhances the system’s ability to penetrate the mucus barrier and disrupt biofilms in mouse models.¹⁴⁷ This intelligent, responsive design allows nanoparticles to dynamically adjust their surface properties according to local microenvironmental changes, simultaneously meeting the seemingly contradictory requirements of “penetration” and “retention”.

Multi-Mechanism Synergistic Strategies to Combat Bacterial Biofilms

Targeting recalcitrant bacterial biofilms in the airways of COPD patients, direct pulmonary antibiotic delivery is hindered by EPS entrapment, while systemic administration carries potential side effects.¹⁶⁸ NDDS, with its programmable and modifiable characteristics, can integrate multiple mechanisms including penetration, bactericidal action, and anti-virulence to achieve synergistic attack on biofilms. For instance, the aforementioned environmentally responsive nanoparticles (DA-AZI-NPs), upon reaching the acidic biofilm microenvironment, undergo charge reversal from negative to positive. This not only enhances electrostatic adsorption to and membrane permeation of bacteria but also triggers degradation of the nanoparticle core by bacterial lipases highly expressed within the biofilm, leading to high-concentration, localized release of the loaded azithromycin in the vicinity of the bacteria.¹³⁷ Another system with a similar mechanism involves immunoantimicrobials constructed from gated peptides encapsulating hollow mesoporous silica nanoparticles. In the acidic biofilm environment, the peptide undergoes charge reversal (negative to positive) and a conformational change (flexible to rigid helical), opening the pores to release loaded ceftazidime in mouse models of COPD. Simultaneously, the transformed peptide forms an alpha-helix that can directly disrupt bacterial membranes and capture bacterial DNA, synergistically killing bacteria and reducing inflammatory cytokine release, thereby mitigating tissue damage.¹²

Notably, common COPD-associated bacteria like Pseudomonas aeruginosa, Haemophilus influenzae, and Klebsiella pneumoniae possess significant quorum sensing (QS) systems. These systems coordinate bacterial population behavior, controlling mechanisms like biofilm formation and virulence factor release, contributing to persistent COPD infection and recurrent exacerbations.^56,176–178 Therefore, delivering QS inhibitors via nanocarriers could potentially attenuate bacterial pathogenicity and biofilm formation at the source, helping to reduce resistance. For example, research has shown that quercetin liposomes not only offer anti-inflammatory and anti-fibrotic therapeutic benefits, but quercetin-chitosan nanocomplexes, with improved solubility and synergistic action with chitosan, can target the QS network regulating motility and biofilm formation, effectively inhibiting P. aeruginosa motility and biofilm formation.^179,180

Beyond traditional antibiotics, nanoparticles themselves can serve as therapeutic agents with novel mechanisms of action. Cu₂O-BSO nanoparticles, via the loaded Buthionine sulfoximine, deplete bacterial glutathione, synergizing with Cu₂O to induce “cuproptosis”-like bacterial death. This directly kills bacteria while downregulating key QS system genes, inhibiting virulence factor expression and biofilm formation.¹⁸¹ They also activate macrophages towards the pro-inflammatory M1 phenotype, enhancing host immune clearance, demonstrating potent efficacy in an MRSA pneumonia model. These multi-mechanism synergistic strategies mark the evolution of NDDS from simple drug carriers to intelligent anti-infective platforms integrating penetration and bactericidal action.

Modulating the Inflammatory and Oxidative Stress Microenvironment

Beyond direct anti-infective functions, NDDS can actively reshape the inflammatory and oxidative stress microenvironment in COPD, enabling multi-dimensional, multi-target synergistic therapy. Firstly, nanocarriers are widely used to efficiently deliver natural antioxidant and anti-inflammatory molecules targeting the core pathological processes of COPD: oxidative stress and chronic inflammation. For example, carboxymethyl chitosan-modified liposomes for delivering oxymatrine and liquid crystalline nanoparticles for delivering curcumin both exhibited stronger anti-inflammatory and antioxidant effects than the free drugs.^182,183 Gallic acid, loaded into nanostructured lipid carriers, showed significantly enhanced bioavailability and active targeting to lung tissue.¹¹⁵ Also, lecithin-coated PLGA nanoparticles for naringin delivery not only significantly enhanced its anti‑inflammatory and antioxidant activities in vitro, but also provided sustained drug release.¹⁸⁴

Notably, NDDS not only enhances the effects of known active ingredients but can also grant them entirely new therapeutic dimensions. 18-β-glycyrrhetinic acid-loaded PLGA nanoparticles not only exerted anti-inflammatory and antioxidant effects but also significantly restored the expression of key antiviral chemokines in bronchial epithelial cells in vitro, effectively counteracting the antiviral immune deficiency caused by cigarette smoke.^185,186 Similarly, lipid–polymer hybrid nanoparticles delivering mitochondrial-targeted antioxidant Mito-TEMPO effectively inhibit mitochondrial reactive oxygen species (ROS) production and modulate antiviral immune responses in vitro.¹⁸⁷ Encapsulation of curcumin in liposomes or mPEG-PLGA nanoparticles significantly enhanced its anti-inflammatory and anti-senescence activities and reversed glucocorticoid resistance by upregulating HDAC2 expression.^188,189 Furthermore, using liquid crystalline nanoparticles to deliver berberine dramatically improved its bioavailability while synergistically inhibiting inflammatory cytokine release, ROS generation, and cellular senescence induced by cigarette smoke or lipopolysaccharide in macrophages and airway epithelial cells, and also attenuated airway remodeling, demonstrating a multi-effect pharmacodynamic synergy.^190–192 Recent research also shows that diacerein, traditionally used for osteoarthritis, can be encapsulated in inhalable oleoliposome dry powders to exert anti-inflammatory effects and be repurposed for treating COPD, highlighting the potential application value of nanotechnology in drug repurposing.¹⁹³

Beyond enhancing known pharmacology, nanocarriers, with their structural programmability, are progressively enabling active, precise intervention in COPD pathogenesis, particularly in two frontier directions: nucleic acid drug delivery and immune microenvironment remodeling. Dry powder inhalable nanocomposite microparticles and cationic polymer nanoparticles can effectively deliver miR-146a to lung cells, silencing the key inflammatory genes interleukin-1 receptor-associated kinase and tumor necrosis factor receptor associated factor 6, achieving upstream regulation.^144,194 Similarly, optimized lipid-polymer hybrid nanoparticles enable efficient delivery of tumor necrosis factor-alpha siRNA into macrophages at a significantly lower dose than free siRNA.¹⁹⁵ Beyond nucleic acids, other studies have used relatively simple PLGA nanoparticles to deliver the proteasome inhibitor ONX-0914. Intranasal administration of these nanoparticles targets macrophages, inhibits their polarization, thereby alleviating airway inflammation and improving lung function in a mouse model.¹¹⁸ Similar active immunomodulatory strategies have also been explored by Oh et al and Wang et al The former utilized hyaluronic acid-modified dendritic mesoporous silica nanoparticles to load nitric oxide donors, while the latter conjugated indole-3-acetic acid onto PAMAM dendrimers.^125,196 Despite differences in carriers and active pharmaceutical ingredients, both studies demonstrated at cellular and animal levels, respectively, that these NDDS effectively alleviate inflammation by promoting macrophage polarization toward the anti-inflammatory M2 phenotype. Zhan et al recently developed a macrophage membrane-coated bimetallic manganese-platinum nanozyme that integrates the targeting ability of a biomimetic membrane with robust multi-ROS scavenging activity. Following intratracheal administration in a COPD mouse model, the system actively homed to the inflammatory microenvironment, providing efficient and sustained ant-inflammatory and antioxidant effects, and attenuating emphysema and airway remodeling.¹⁴⁸ By targeting the upstream inflammatory and oxidative stress drivers of EMT, these strategies contribute to mitigating the functional impairments caused by epithelial–mesenchymal niche dysregulation.

Interestingly, recent study has revealed that conventional ionizable cationic LNP carriers possess intrinsic immunogenicity, which can trigger inflammatory responses upon pulmonary delivery and upregulate the expression of MUC5AC, thereby compromising therapeutic efficacy.¹⁴⁹ To address this “carrier paradox”, Zhao et al developed a non‑inflammatory LNP for the delivery of MUC5AC-targeting siRNA. This nanoparticle was designed with three synergistic features: the use of low‑immunogenicity ionizable cationic lipids, the incorporation of the pentacyclic triterpenoid ursolic acid as an anti-inflammatory component, and optimization of the nitrogen-to-phosphorus ratio to enhance biocompatibility. This design intrinsically circumvents carrier-induced inflammatory side effects. In both an asthma mouse model and a COPD patient-derived lung organoid model, the system demonstrated potent MUC5AC silencing efficacy, leading to marked alleviation of airway inflammation and mucus hypersecretion.¹⁴⁹

Promoting Tissue Repair and Regeneration

Addressing elastin degradation, a key pathological feature of emphysema, LNPs loaded with the synthetic retinoid Am80 using the SS-cleavable proton-activated lipid-like material O-Phenyl-P4C2 (SS-OP) enabled targeted delivery to retinoic acid receptors in the nuclei of alveolar epithelial cells via endocytosis.^150,197 At an extremely low dose (0.01 mg/kg), this system achieved structural repair of alveolar collapse in an elastase-induced mouse emphysema model. The SS-OP carrier also delivers 1α,25-dihydroxyvitamin D₃ to nuclear vitamin D receptors in alveolar epithelial cells, achieving alveolar regeneration.¹⁹⁸ Another study designed albumin nanoparticles loaded with penta-galloyl glucose and conjugated with an anti-elastin antibody. Upon inhalation, these nanoparticles targeted and accumulated in areas of degraded lung elastin, effectively protecting the elastin network by inhibiting matrix metalloproteinase-12 activity, significantly improving lung compliance and tidal volume.¹⁹⁹ Beyond the aforementioned protective strategies, NDDS can also directly activate endogenous epithelial regenerative programs at the genetic level. Chen et al constructed hepatocyte growth factor mRNA-loaded lipid nanoparticles that, upon aerosol inhalation, activated epithelial regenerative pathways and reversed alveolar structural damage in two emphysema mouse models.¹⁵¹

Compared to the fully synthetic nanocarriers mentioned above, extracellular vesicles (EVs), as natural nanoparticles secreted by cells, possess inherent biocompatibility, excellent low immunogenicity, and innate cell targeting and communication capabilities.²⁰⁰ Through engineering modifications, they can be endowed with potent therapeutic functions. For instance, engineered EVs surface-anchored with Wnt3a protein, administered intravenously, activated the Wnt/β-catenin regenerative pathway in alveolar epithelial cells, promoting proliferation and inhibiting apoptosis.²⁰¹ These EVs synergistically modulated epidermal growth factor receptor and other repair signaling pathways, activating endogenous regenerative programs and improving lung function. Of note, the study explicitly revealed that most intravenously injected EVs are trapped in the liver, with only limited pulmonary distribution, further reinforcing the translational merits of inhaled administration. Overall, current regenerative strategies predominantly address isolated components of complex structural injury. Future endeavors may integrate the EMT pathological network to engineer multi-targeted nanoplatforms that concurrently activate reparative pathways and restrain pathological remodeling, steering nanotherapeutics toward a paradigm shift of active disease modification.

Reversing Treatment Resistance and Addressing Disease Heterogeneity

Nanotechnology-enabled precision intervention also offers opportunities to overcome treatment resistance and address disease heterogeneity by restoring dysregulated pathways at the genetic and epigenetic level. For example, as mentioned earlier, curcumin reverses treatment resistance precisely by upregulating the key protein HDAC2.¹⁸⁸ Chikuma et al developed core-shell lipid-polymer nanoparticles capable of co-delivering the antioxidant manganese porphyrin dimer and an HDAC2-encoding plasmid. These nanoparticles scavenge excess ROS, alleviating oxidative stress, while simultaneously replenishing the deficient HDAC2 protein, restoring its inhibitory function on inflammatory gene transcription, thereby fundamentally reversing glucocorticoid resistance.¹⁵²

Furthermore, COPD heterogeneity also demands targeting specific cell subpopulations. As previously noted, nanoparticles can directly mediate immunomodulation by targeting specific cells like neutrophils or macrophages.^{106,118,125,145} Beyond immune cells, senescent cells are another crucial cell subpopulation driving COPD pathogenesis. Senescent fibroblasts persistently secrete a plethora of senescence-associated secretory phenotype factors, fueling chronic inflammation and tissue destruction, thus promoting COPD progression.^202,203 Targeting this key cell type, researchers designed self-assembling DNA nanotubes capable of efficiently delivering FOXO4 siRNA to cigarette smoke-induced senescent lung fibroblasts. By modulating the BCL2/BAX apoptotic pathway, this system achieved selective clearance of these senescent cells with minimal effects on normal cells.²⁰⁴

Despite these exploratory efforts, research specifically targeting COPD treatment resistance with nano-delivery systems remains relatively limited, and most strategies still focus on indirect intervention through anti-inflammatory and antioxidant mechanisms. This difficulty partly stems from the complexity of GC resistance mechanisms, involving receptor expression, post-translational modifications, epigenetics, and microenvironmental signaling networks. Therefore, modulating a single target may be insufficient to block the entire cascade.^205,206 This necessitates not only a deeper dissection of the GC resistance molecular network by researchers but also places higher demands on NDDS to achieve multi-target, temporally sequenced, and synergistic drug delivery.

Formulation Innovations for Improved Patient Adherence

NDDS offers practical solutions to enhance patient adherence by optimizing dosage forms and devices, achieving long-acting/intelligent release, and enabling theranostics.

Integrating nanotechnology successfully into familiar and easy-to-use inhalation devices is the crucial first step towards clinical translation.²⁰⁷ Research indicates that through formulation and process design adjustments, functionalized nanoparticles can be stably loaded into metered-dose inhalers while maintaining good aerodynamic performance and in vitro cytocompatibility, preliminarily validating the feasibility of scaled-up production. In the field of dry powder inhalers, advanced particle engineering techniques (eg, spray drying) can produce nanostructured dry powders with good flowability and dispersibility.^157,163,208 These well-engineered particle designs can help reduce patients’ dependence on peak inspiratory flow rate, making administration more likely to succeed and thus reducing treatment failures due to incorrect use, optimizing the medication experience from a technical perspective.²⁰⁹

In the fabrication of nanostructured dry powders, Anaya et al combined a 3D-printed microfluidic mixer with spray drying to produce inhalable azithromycin microparticles with precisely controllable aerodynamic properties. These microparticles achieved a high fine particle fraction and effective deep lung deposition at both 30 L/min and 60 L/min flow rates, demonstrating the robustness of the formulation across different patient inspiratory capacities.²¹⁰ This integration of advanced manufacturing techniques represents a promising direction for ensuring batch-to-batch reproducibility in nanoformulation production.

Regarding innovation in inhalation platforms, preliminary studies have explored the feasibility of combining nanoformulations with electronic nicotine delivery systems. One study confirmed that an electronic cigarette could deliver beclomethasone dipropionate nanocrystals in aerosol form.²¹¹ This concept provides an important reference for improving adherence, especially in COPD patients with a smoking history: Firstly, leveraging the morphological and operational similarity of e-cigarettes to conventional cigarettes may enhance patient acceptance. Secondly, the simple “push-button” operation reduces the need for complex breath-coordination techniques, making it more suitable for elderly or physically limited individuals. Thirdly, integrating the dosing behavior with the patient’s existing smoking habit could help naturalize treatment into daily life, promoting long-term regular medication use. Although this research is still at the proof-of-concept stage, it suggests that future device design for inhaled nanoformulations should prioritize user-friendliness, operational simplicity, and integration with behavioral habits to optimize both efficacy and treatment experience.

Optimizing the carrier design can significantly enhance drug delivery efficiency and therapeutic effect. Using a Quality by Design approach to systematically optimize the formulation of budesonide lipid-polymer hybrid nanoparticles enables precise control over formulation performance under the guidance of identified critical quality attributes (eg, particle size, zeta potential, encapsulation efficiency), improving drug loading efficiency and batch-to-batch consistency.²¹² Other studies show that carrier optimization can directly improve pharmacodynamics. For example, loading beclomethasone dipropionate into novel liposomes modified with hyaluronic acid and mucin resulted in more effective deposition and resistance to oxidative stress.²¹³ In another instance, forming an inclusion complex of budesonide with hydroxypropyl-β-cyclodextrin enhanced anti-inflammatory potency through a unique mechanism involving interference with cholesterol microdomains in cell membranes.²¹⁴ These carrier systems effectively improve the pulmonary deposition and therapeutic efficacy of glucocorticoids, which helps bolster patient confidence in the treatment regimen and thereby promotes long-term adherence.

In addition, the development of long-acting sustained-release systems based on nanotechnology holds the potential to fundamentally reduce dosing frequency. Using polyvinyl alcohol-modified chitosan nanoparticles to deliver budesonide not only improved its solubility but also demonstrated significant long-term sustained-release effects.²¹⁵ Similarly, Tessier et al synthesized poly(malic acid)-budesonide polymer-drug conjugates, which, following self-assembly and spray drying into microparticles, achieved a high drug loading of up to 73% and favorable alveolar deposition, enabling sustained budesonide distribution in the lungs of healthy rats for up to 48 hours while retaining anti-inflammatory activity.¹⁴⁰ Siddheshwar et al developed myricetin-loaded inhalable microspheres that achieved sustained release for over 12 hours and favorable aerodynamic performance, producing 63.47% tracheal relaxation at a concentration of 25 μg/mL, while maintaining remarkable stability for six months under both accelerated and real-time storage conditions.¹⁵³ More complex multi-stage microparticle designs could further extend the duration of action. For instance, Mejías et al constructed a multi-stage enzyme-responsive nanogel system for pulmonary drug delivery, where inner nanoparticles act as drug carriers and an outer microgel serves as a carrier for pulmonary deposition, prepared under mild conditions.¹³⁸ The microgel is composed of polymers responsive to trypsin and neutrophil elastase, exhibiting size tunability and enzyme responsiveness, avoiding early macrophage clearance, showing slow clearance in healthy lungs (>24h), and enabling rapid drug release in the disease microenvironment (<30min). Such sustained-release nanoformulations could theoretically simplify multiple daily doses to once daily, significantly reducing the treatment burden of long-term medication and representing one of the most promising directions for improving patient adherence.

An even more ideal scenario involves integrating disease monitoring for closed-loop management. For example, Tu et al developed a wearable wireless patch capable of real-time monitoring of the inflammatory marker C-reactive protein in sweat.²¹⁶ If this technology could be linked with intelligent nano-delivery systems in the future, it could guide patients to intervene early upon detecting inflammation, optimizing fixed-schedule dosing to precision dosing based on biomarker feedback, thereby greatly enhancing treatment efficiency and patient engagement. Another study prepared glycine-coated superparamagnetic iron oxide nanoparticles. These nanoparticles simultaneously enabled non-invasive pulmonary magnetic resonance imaging and specific targeting of alveolar macrophages/neutrophils without inducing inflammation, offering an integrated solution for lesion visualization, targeted drug delivery, and post-administration distribution assessment, paving the way for precision intervention and therapeutic monitoring.²¹⁷

Current Clinical Research Status and Translational Challenges of NDDS

Current Status of Clinical Research on Nanomedicines for COPD

Despite ample preclinical evidence demonstrating the potential of NDDS in overcoming multiple clinical challenges of COPD, its clinical translation lags significantly behind. Currently, pulmonary nanoformulations that have entered clinical trials are mostly focused on lung malignancies (eg, non-small cell lung cancer, small cell lung cancer) and acute infectious diseases (eg, COVID-19), with dedicated studies for COPD remaining scarce. The following table summarizes some clinical studies using nanoformulations for COPD and diseases with related pathophysiological mechanisms (Table 4).

Table 4.

Clinical Studies of Nano-Formulations for COPD and Related Respiratory Diseases

NCT Number	Nanocarrier	Drug Loaded	Condition/Disease	Phase	Key Findings/Notes	References
NCT06439875	Liposomes	L-Arginine, Vitamin C	COPD, Respiratory Failure	Phase II	Investigating the role of L-arginine and liposomal vitamin C during pulmonary rehabilitation; results pending.	[218]
NCT01315678	Amikacin Liposome	Amikacin	Cystic Fibrosis with Pseudomonas aeruginosa Infection	Phase III	Compared efficacy and safety of liposomal amikacin vs inhaled antibiotic tobramycin.	[219,220]
NCT01315236	Amikacin Liposome	Amikacin	Mycobacterium avium Complex Lung Infection	Phase III/IV	Collecting real-world data to evaluate liposomal amikacin efficacy in refractory non-tuberculous mycobacteria; previous pivotal study demonstrated superior microbiological conversion in M. abscessus complex, but this is an observational study with limited evidence level.	[221,222]
NCT03657342 (BOSTON-1) NCT03656926 (BOSTON-2)	Liposomal Cyclosporine A	Cyclosporine A	Bronchiolitis Obliterans Syndrome	Phase III	Inhaled liposomal cyclosporine A + standard of care significantly slowed FEV1 decline (~50%); some patients showed stabilized/improved lung function. Limitations: small study population; requires a specific vibrating mesh nebulizer (treatment burden); long-term efficacy and survival impact unknown.	[223,224]
NCT05938946	Liposomes	Treprostinil	Pulmonary Arterial Hypertension	Phase I	Evaluating safety, tolerability, and pharmacokinetics of single-dose L608 (liposomal treprostinil inhalation solution) in healthy adults.	[225]
NCT04602442 NCT04491240	Exosomes	Mesenchymal Stem Cell-derived Exosomes	COVID-19 Pneumonia / SARS-CoV-2 Pneumonia / ARDS	Phase I/II	Evaluated nebulized exosomes as adjunctive therapy for moderate/severe COVID-19 pneumonia; showed good safety and trends towards improved inflammatory markers. Limitations: small sample size; some results not statistically significant.	[226, 227]
NCT04602104	Exosomes	Mesenchymal Stem Cell-derived Exosomes	ARDS	Phase I/II	Evaluating safety of nebulized exosomes for ARDS; early exploratory study; optimal dose and definitive efficacy not established.	[228]
NCT04378920 NCT06640777	Liposomal transcrocetin	Transcrocetin	ARDS	Phase IIa/III	Completed studies reported good safety. Phase IIa showed trends towards reduced inflammatory biomarkers (eg, interleukin-6) and possibly improved oxygenation. Efficacy being further investigated in Phase III.	[229,230]
NCT02583373 NCT05776004	Liposomes (CAL02)	Pathogen Toxin Capture Agent	Pneumococcal Pneumonia	Phase II/III	Acts as antibiotic adjunctive therapy by neutralizing bacterial toxins to reduce excessive lung inflammation and organ damage. Earlier studies showed reduced inflammatory markers and improved clinical outcomes; Phase III results pending.	[231–233]
NCT04482595	Nanoparticles (BIO 300)	Genistein Analog	Post-COVID-19 Pulmonary Fibrosis	Phase II	Interim analysis suggests oral BIO 300 (nanocrystalline formulation) may improve quality of life scores and inflammatory markers in some COVID-19 survivors; primary endpoint data pending.	[234]
NCT03059017	Niosomes	Salbutamol Sulfate	Pulmonary Drug Delivery	Phase I	Salbutamol niosomes significantly prolonged pulmonary drug action time; study was formulation exploration only, not tested for efficacy in patient disease models.	[235]
NCT01515007 (ORBIT-3) NCT02104245 (ORBIT-4)	Liposomes	Ciprofloxacin	Non-Cystic Fibrosis Bronchiectasis with Chronic Pseudomonas aeruginosa Infection	Phase III	Inhaled liposomal ciprofloxacin showed potential in delaying time to first pulmonary exacerbation in ORBIT-4 (positive post-hoc analysis). However, ORBIT-3 was negative, and pooled analysis did not meet the primary endpoint.	[236–239]

Abbreviations: ARDS, Acute Respiratory Distress Syndrome; COPD, Chronic Obstructive Pulmonary Disease; COVID-19, Coronavirus Disease 2019; FEV₁, Forced Expiratory Volume in 1 second; NCT, National Clinical Trial; SARS-CoV-2, Severe Acute Respiratory Syndrome Coronavirus.

According to searches on the U.S clinical trials registry (https://clinicaltrials.gov/), existing clinical research on nano-delivery directly targeting COPD is extremely limited. Currently, only one Phase II trial (NCT06439875) investigates oral liposomal L-arginine and vitamin C in COPD patients with chronic respiratory failure during pulmonary rehabilitation, with results pending. Similarly, Harrell et al reported that the mesenchymal stem cell-derived exosome product Exo-d-MAPPS (Exosome-derived Multiple Allogeneic Protein Paracrine Signaling) could reduce airway inflammation in COPD patients and mouse models via its carried immunomodulatory factors. However, this product essentially utilizes exosomes as natural carriers of active molecules for direct anti-inflammatory effects, rather than being an actively drug-loaded nano-delivery system. Its clinical translation pathway differs significantly from synthetic nanocarriers, and the study lacked a registered clinical trial number, limiting its reference value.²⁴⁰

The vast majority of relevant studies focus on COPD complications or other respiratory diseases sharing common pathological mechanisms. For instance, the inhaled liposomal amikacin formulation (ARIKAYCE^®) (NCT01315236) for non-tuberculous mycobacterial lung infection, with its mechanism targeting biofilms and intracellular infection, holds some relevance for managing chronic bronchial infection in COPD. This is currently the only successfully marketed inhaled LNP drug. Its successful market approval can be attributed to its precise design perfectly matching the therapeutic bottleneck of non-tuberculous mycobacterial lung disease. Mechanistically, its core advantage lies in the liposomal nanocarrier’s ability to effectively penetrate mycobacterial biofilms and be efficiently phagocytosed by alveolar macrophages, delivering high concentrations of amikacin directly into macrophages, effectively clearing intracellular bacteria inaccessible to traditional antibiotics, fundamentally addressing treatment resistance.²²¹ From a formulation and usability perspective, the innovation of liposomal amikacin also lies in combining the liposome with a dedicated nebulizer system (Lamira^®) to create an integrated delivery solution. This nebulizer is specifically designed to generate an aerosol with an optimal particle size (approx. 3.0–5.0 μm), ensuring efficient deposition of liposomal particles in the alveolar and small airway regions, achieving a pharmacokinetic profile of high lung exposure and low systemic exposure.²⁴¹ The successful approval of liposomal amikacin confirms that LNPs can safely and effectively deliver drugs via inhalation to deep lung tissue, providing a key technological paradigm for the clinical translation of COPD nanoformulations. However, this paradigm cannot solve the core treatment problem of COPD, as COPD is not a single-pathogen-driven infectious disease but a complex chronic syndrome involving multiple intertwined pathological axes: dysregulated inflammatory cascades, redox imbalance, and progressive airway remodeling.²⁴² Therefore, merely clearing pathogens cannot reverse the disease process of COPD.

Additionally, some studies targeting related conditions like inflammation, infection, and fibrosis (eg, NCT03657342, NCT02104245) offer insights for COPD treatment, but the therapeutic goals for these diseases still differ significantly from COPD and cannot fully represent or solve its treatment challenges. Moreover, most of these trials are Phase I/II, with small sample sizes, primarily focusing on preliminary indicators like safety and pharmacokinetics, lacking large-scale Phase III efficacy validation, and possessing certain limitations. The divergent results of the ORBIT-3 and ORBIT-4 Phase III studies also provide valuable reverse thinking for COPD nano-formulation development. They demonstrate that even in bronchiectasis, targeting a single pathogen, efficacy assessment can yield “false-negative” or “positive” differences depending on endpoint selection and analysis methods.²³⁶ This implies that for a highly heterogeneous syndrome like COPD, focusing solely on a single target or using traditional endpoints in clinical trials risks masking true efficacy due to population heterogeneity or inappropriate assessment timing. Therefore, clinical study design for COPD nanomedicines must be more cautious, incorporating dynamic, multi-dimensional endpoints from the early trial design phase.

Analysis of Translational Challenges for NDDS

Overall, the translational imbalance for COPD nanoformulations stems from multiple reasons. Firstly, there is a misalignment between market orientation and R&D investment. The field of lung cancer, with its well-defined tumor targets, relatively clear clinical endpoints (eg, tumor response rate, survival), and higher medical economic value, attracts substantial funding and innovative technology, with numerous clinical trials accumulating rich safety and efficacy data. The COVID-19 pandemic spurred explosive growth in nanovaccines (eg, NVX-CoV2373) and antiviral formulations targeting viral infections. In contrast, COPD has a long disease course, complex pathophysiology, and its clinical endpoints are often “softer” measures like rate of lung function decline, exacerbation frequency, and quality of life. This makes clinical validation of new therapies lengthy, costly, and high-risk, reducing developers’ willingness to invest in high-risk nanomedicines.

Secondly, limitations in preclinical disease models for COPD further exacerbate the preclinical-clinical translation gap. Many nanoformulations showing anti-inflammatory or antioxidant efficacy in animal models (eg, smoke exposure models) face challenges when progressing to human trials. While animal models are indispensable for studying pathological mechanisms and initial drug screening, no current model fully replicates the heterogeneity, complex pathological network, and full disease progression of human COPD.²⁴³ On the other hand, although in vitro models that mimic the biological characteristics of the human lung are continuously evolving, each still has its own limitations when applied to the evaluation of inhaled nanoformulations. For example, the most commonly used air-liquid interface cell culture model, although it effectively recapitulates the epithelial barrier for preliminary screening of nanoformulation permeability, is inherently a static culture system and thus cannot mimic drug deposition and clearance processes under dynamic respiratory physiological conditions.^244,245 Lung organoids formed via 3D self-assembly possess multicellular architecture with cell polarity and can recapitulate COPD pathological phenotypes in patient‑derived models; however, their anatomical configuration limits their applicability for evaluating inhaled drug delivery.^246,247 In contrast, the microfluidic lung-on-a-chip, currently the most biomimetic in vitro platform, simultaneously recreates three core physiological features—air-liquid interface, respiratory-like mechanical stretching, and perfusion—yet is constrained by complex fabrication processes and low throughput.²⁴⁸ Such inter-model heterogeneity may lead to inconsistent data on penetration rates, cellular uptake, and other parameters for the same nanoformulation across different platforms, thereby reducing the credibility of extrapolating from a single simplified model to real-world clinical scenarios.^249,250

Thirdly, the COPD patient population exhibits extreme clinical and biological heterogeneity. This is not only a challenge for precision therapy but also a core difficulty in patient recruitment for translational research. Patients differ not only in clinical phenotypes and severity but also significantly in underlying pathobiological mechanisms. Studies show that COPD patients have, on average, 5.4 “treatable traits” requiring simultaneous management, spanning pulmonary, systemic, and behavioral/psychological domains, all interconnected and influencing disease progression.^251,252 This complex heterogeneity creates a significant gap between trial inclusion criteria and the real-world patient population. From the disease perspective, the high prevalence of multimorbidity (eg, cardiovascular disease, diabetes) in patients can both influence trial outcomes and often leads to exclusion by stringent trial criteria. This makes traditional “one-size-fits-all” inclusion criteria, based on fixed lung function thresholds or exacerbation history, inadequate for recruiting patients representative of the broad heterogeneous population. From a trial execution perspective, the requirement for high-quality pulmonary function tests, induced sputum analysis, and other complex endpoint assessments limits the number of qualified research centers. Furthermore, there is a mismatch in healthcare resources: severely ill patients suitable for complex intervention research are often unstable or do not meet comorbidity criteria, while the large population of stable patients in the community struggles to access top-tier research centers.^252,253 These multi-level barriers collectively result in high screen failure rates, prolonged recruitment periods, and high trial costs, slowing the progress of clinical research for new COPD therapies, especially nanomedicines requiring precise patient stratification.

Fourthly, as “drug-carrier” complexes, nanoformulations are more complex to characterize, quality control, and assess for safety than traditional drugs. Minor deviations in manufacturing processes can lead to significant changes in critical quality attributes (eg, particle size distribution, drug loading), impacting efficacy and safety. Regulatory frameworks and bioequivalence standards for nanomedicines are still being explored and refined globally. This uncertainty poses significant regulatory risks and additional costs for developers. The core challenges primarily manifest in bioequivalence assessment and long-term safety. Because nanocarriers can significantly alter a drug’s in vivo distribution, release kinetics, and bioavailability, traditional bioequivalence approaches based on systemic exposure pharmacokinetics are often inapplicable. Therefore, regulatory agencies like the US FDA are promoting alternative pathways based on in vitro testing and modeling.^254,255 However, the current critical bottleneck is the lack of fully validated and standardized in vitro methods to reliably predict the complex in vivo behavior of nanomedicines. Specifically, the slow and variable inspiratory flow patterns of COPD patients significantly alter aerosol spray characteristics and deposition sites, rendering the constant‑flow testing of conventional Next Generation Impactors inadequate for predicting true pulmonary deposition.²⁵⁶ Upon airway entry, nanoparticles acquire a biomolecular corona that profoundly modulates their cellular uptake and targeting, yet routine in vitro release assays typically overlook this dynamic process, failing to accurately reflect the structural stability and drug release behavior of nanoparticles in the airways.^257–259 Regarding uptake and clearance, the dynamic airflow shear forces in the lungs significantly influence macrophage uptake of nanoparticles, and the impaired phagocytic function of macrophages under COPD pathological conditions, which together limit the reliability of in vitro macrophage phagocytosis models in predicting the in vivo clearance of nanoparticles.^260–263 These inherent limitations of current in vitro testing methodologies collectively undermine the establishment of robust in vitro‑in vivo correlations for inhaled nanoformulations.

Beyond this, for a disease like COPD requiring lifelong management, long-term safety considerations pose a unique translational barrier for nanomedicines. The potential for long-term lung retention of the nanocarrier itself, the safety of biodegradation products, and interactions with the complex pulmonary microenvironment could raise long-term risks not associated with traditional drugs. For instance, a study on inhalable ciprofloxacin/poly(2-ethyl-2-oxazoline) nanoparticles showed enhanced bactericidal effects against respiratory pathogens and acceptable low toxicity towards bronchial epithelial cells, but exhibited relatively high cytotoxicity towards lung macrophages.²⁶⁴ However, early exploratory clinical studies systematically evaluating the long-term retention behavior, immunogenicity, and effects of slowly degrading products of these nanomaterials in COPD patients are severely lacking. This makes extrapolating from preclinical safety data to long-term human use highly uncertain, greatly hindering the confidence of both developers and regulators in decision-making.

In summary, the clinical translation of NDDS in COPD remains in its early infancy. The key to advancing the field lies in translating preclinically proven nano-delivery strategies into clinical evidence that clearly improves long-term patient outcomes through well-designed clinical trials (eg, targeting specific COPD phenotypes, enriching populations using biomarkers). This requires collaborative efforts from academia, industry, and regulatory agencies to bridge the gap from “potential” to “practice”.

Discussion

The true potential of NDDS in COPD lies not merely in improving drug delivery, but in enabling a fundamental shift in the therapeutic paradigm. This represents a move from macroscopic, generalized symptom control towards microscopic, precise intervention rooted in disease pathophysiology. This paradigm shift manifests on three levels: Firstly, strategically, NDDS upgrades “drug delivery” to “pathological environment programming”. As discussed above, NDDS possess a dual capacity: they passively respond to COPD microenvironmental cues (eg, pH, protease, ROS),^{12,137,138,152} and actively target specific cells or markers via ligand or membrane engineering.^106,111,145 This synergy enables NDDS to precisely deliver therapeutic power to critical nodes in the complex pathological network. Secondly, in terms of objectives, therapy shifts towards the coordinated modulation of multiple cores, including inflammation, oxidative stress, protease imbalance, and tissue remodeling. Ultimately, leveraging their programmable nature, NDDS hold the potential to be tailored to individual patient characteristics, advancing COPD management toward personalized precision therapy. To realize this vision and bridge the gap from bench to bedside, future developments could focus on the following frontier directions:

AI-Driven Rational Design and Optimization of Smart Nanoparticles: The advancement of AI is profoundly impacting the entire process of nanoformulation R&D and application. In the early research design phase, AI provides multifaceted assistance. For instance, Zhang et al developed a machine learning model that achieved 91.89% accuracy in predicting the co-assembly capability of nonsteroidal anti-inflammatory drugs and chemotherapeutic agents. This model facilitates the bypass of complex synthetic steps associated with conventional nanocarriers and offers a new paradigm for the development of carrier-free nanoformulations for multi-drug combination therapy in COPD.²⁶⁵ Concurrently, the integration of AI with computational fluid dynamics enables the simulation of nanoparticle movement and deposition within the abnormally narrowed and complex airways of COPD patients, allowing for virtual screening of optimal particle size, shape, and surface property formulations while reducing experimental trial-and-error costs.¹¹ In the carrier engineering stage, AI has evolved from single-parameter prediction to high-throughput discovery and multi-module integration. Specifically, Witten et al created a dataset containing over 9,000 LNP activity measurements and trained a directed message‑passing neural network to predict nucleic acid delivery efficiency based on different lipid structures. Through in silico evaluation of 1.6 million lipids, they identified two lead LNP candidates, FO-32 and FO-35, that efficiently delivered messenger RNA to the lungs of mice and ferrets, demonstrating the potential of deep learning in enhancing nanoparticle delivery efficacy.²⁶⁶ Building upon this, an integrated multi-step AI workflow has been successfully applied to the joint design of targeting ligands and core-shell nanocarriers, achieving synchronous delivery of synergistic drug pairs with distinct mechanisms of action through programmable spatial allocation.²⁶⁷ This AI-guided “spatial programming” strategy holds promise for coordinating multiple therapeutic axes in COPD treatment, including inflammation, oxidative stress, and infection. In the biodistribution and efficacy validation phase, AI-assisted imaging and evaluation technologies are revolutionizing the in vivo assessment of nanomedicines. Recently developed AI-powered three-dimensional whole-lung imaging ecosystems enable panoramic, quantitative mapping of nanoparticle deposition across bronchial and alveolar regions at single-cell resolution, allowing precise evaluation of nanoparticle distribution differences across various delivery modalities.²⁶⁸ In the efficacy assessment dimension, Cao et al developed a ROS-responsive metal-free nanozyme and utilized a fluorescence micro-optical sectioning tomography system to acquire three-dimensional pathological maps of the entire lung, coupled with machine learning for high-throughput analysis of massive images to automatically identify inflammatory cells and quantify tracheal wall thickness.²⁶⁹ This approach enables cross-scale, visualized precision evaluation of nanomedicine biodistribution and therapeutic outcomes.²⁶⁹ In summary, these “intelligent design-screening-validation” strategies significantly accelerate the development of optimal nanoformulations.

Patient Stratification and Precision Matching Based on Multi-Omics Biomarkers: As previously noted, the high heterogeneity of COPD is one of the important reasons for differences in treatment responses, and integrating multi-omics technologies for patient stratification offers a feasible direction to address this issue. At the genomic level, the combined application of polygenic risk score and blood transcriptional risk score has successfully defined high-risk COPD subtypes with distinct genetic backgrounds and molecular characteristics in the COPDGene and ECLIPSE cohorts.⁶⁷ At the transcriptomic and epigenomic levels, Olvera et al employed a multilayer network analysis integrating mRNA, microRNA, and methylome data from lung tissue samples of 135 former smokers with COPD, identifying five molecularly distinct patient communities that were significantly associated with clinical parameters including forced expiratory volume in 1 second (FEV₁) and blood eosinophil counts.²⁷⁰ Notably, this study further revealed that patients with similarly low FEV₁ and emphysema were found to have molecularly distinct small airway and immune response patterns. At the immunoinflammatory phenotyping level, Bordag et al performed machine learning-assisted multilevel immune profiling and identified a unique COPD immune subtype characterized by specific immune cell infiltration and elevated cytokines, which was associated with increased emphysema severity independent of GOLD stage.²⁷¹ Collectively, these multi-omics findings demonstrate that the molecular heterogeneity of COPD profoundly influences disease progression trajectories. This recognition carries profound implications for the clinical translation of NDDS: a nanomedicine effective against one molecular subtype may be entirely ineffective in another. The pathway from stratification to targeted intervention has already received preliminary clinical validation: the Phase III BOREAS trial demonstrated that in COPD patients with type 2 inflammation, as indicated by a blood eosinophil count of ≥300 cells/μL, the anti–IL-4/IL-13 monoclonal antibody dupilumab reduced the annualized rate of moderate or severe exacerbations by 30% and significantly improved lung function and quality of life.²⁷² These findings suggest that future clinical trials of COPD nanotherapeutics could enroll patients based on molecular stratification, matching distinct NDDS strategies to different patient subtypes to ensure precise alignment between the treated population and the drug’s mechanism of action.

Multifunctional NDDS to Address Pulmonary Comorbidities: The clinical course of COPD is often significantly complicated by coexisting respiratory comorbidities, substantially increasing therapeutic challenges.²⁷³ A survey of 3,913 COPD patients revealed that 44.7% had at least one comorbidity, and 6.4% had three or more concurrent conditions.²⁷⁴ Common respiratory comorbidities, such as asthma-COPD overlap, affect approximately 14–24% of COPD patients and are associated with higher exacerbation risk and poorer lung function. Serious comorbidities like lung cancer represent a fatal threat to these patients.^275–278 A meta-analysis including 613,373 COPD patients reported a pooled lung cancer incidence of 6.0% in this population.²⁷⁹ These comorbidities not only adversely affect prognosis but also complicate pharmacotherapy: multiple studies indicate that more than half of COPD patients are on polypharmacy (≥ 5 drugs), significantly increasing the risk of drug–drug interactions and adverse drug reactions.^280–282 Targeted NDDS, with its highly programmable carrier structures, flexible drug loading capabilities, and surface functionalization platforms, offer a novel technological pathway for integrated comorbidity intervention: On one hand, by constructing multifunctional integrated nanoplatforms, anti-inflammatory/antioxidant drugs can be co-loaded with chemotherapeutic agents, antibiotics, or immunomodulators, enabling spatiotemporally coordinated intervention on multiple pathogenic targets within the same carrier.^106,111,125 For instance, iguratimod loaded into nanostructured lipid carriers and administered via nebulization simultaneously improved airway inflammation, oxidative stress, and lung function impairment in an Asthma-COPD Overlap model.²⁸³ On the other hand, future research could utilize dual-targeting ligand modifications or biomimetic membrane camouflage strategies to engineer nanoparticles capable of simultaneously recognizing tumor cells and inflammation-associated fibroblasts, or simultaneously targeting bacterial biofilms and activated macrophages, thereby achieving “two birds with one stone” precision therapy in COPD-comorbidity settings.^12,284 This multi-targeting strategy enables nanosystems to better address the complex pathological microenvironment of comorbid conditions and achieve synergistic modulation of multiple pathogenic pathways within the disease network.

Conclusion

In summary, the advantage of NDDS lies in providing a programmable therapeutic platform whose design flexibility precisely matches the complex demands imposed by the multifaceted clinical challenges of COPD. Through functional modifications enabling precise targeting of lesions, combined with co‑loading of multiple drugs and sequential release designs, NDDS can transcend single‑target intervention and achieve comprehensive modulation of multiple pathogenic links. Although preclinical studies have demonstrated their therapeutic potential in various disease models, the clinical translation of NDDS still faces dual translational bottlenecks arising from the inherent complexity of human COPD and the intrinsic properties of nanomedicines. Current research has explored these bottlenecks through directions such as AI assistance and upgrading preclinical models. Future development should leverage multidisciplinary collaboration involving materials science, computational science, biology, and clinical medicine to construct intelligent co‑delivery platforms, thereby translating current proof‑of‑concept achievements into clinically feasible therapies for COPD.

Disclosure

The authors report support for the manuscript from Sichuan Hospital Association, during the conduct of the study. The authors report no conflicts of interest in this work.