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Application of Nanomaterials in Pulmonary Drug Delivery

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A special issue of Pharmaceutics (ISSN 1999-4923). This special issue belongs to the section "Nanomedicine and Nanotechnology".

Deadline for manuscript submissions: 20 May 2026 | Viewed by 25833

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Dr. Ivana D'Angelo

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Guest Editor

Department of Environmental, Biological and Pharmaceutical Sciences and Technologies, University of Campania “Luigi Vanvitelli”, 81100 Caserta, Italy
Interests: drug delivery; pharmaceutical technology; polymeric micro/nanoparticles; micro- and nanoemulsions; transmucosal and pulmonary drug delivery; antimicrobial delivery

Dr. Ravi Maharjan

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Guest Editor

Laboratory of Biopharmaceutics, Yonsei University, Songdo, Incheon 21983, Republic of Korea
Interests: mRNA vaccines; lyophilization; vaccine stability; continuous manufacturing
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Special Issue Information

Dear Colleagues,

Drug delivery to the lung through nanomaterials is considered a promising approach that may offer new opportunities to boost the research and marketing of inhaled products as well as enhance clinical responses in both local and systemic treatments. Due to the efficiency of lung clearance mechanisms and the multiple barriers imposed by the lungs, control of nanoparticle physicochemical properties, such as size, shape, surface and aerodynamic properties, is mandatory for improving stability of the drug in lungs and promote its transport across extracellular and cellular barriers. To achieve effective drug pulmonary delivery, optimized nanomaterials can be obtained by merging the appropriate materials and production techniques. Recent advances in nanotechnology have provided promising solutions in this field; nevertheless, there are still important issues to address and clarify, such as nanoparticle stability, mucociliary and phagocytic clearance, immunogenicity, toxicity and lung accumulation after inhalation.

This Special Issue aims to highlight current research advances in the design and development of inhalable nanomaterials, with a special focus on novel technological strategies capable of improving the compatibility of nanoparticles with the lung milieu and, thus, their safety and effectiveness.

Dr. Ivana D'Angelo
Dr. Ravi Maharjan
Guest Editors

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Keywords

nanomaterials
lung delivery
inhalable formulations
nanoparticle properties
aerosolization
nanoparticle/mucus interactions

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Published Papers (10 papers)

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Research

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28 pages, 4434 KB

Open AccessArticle

From Bacterial Extract to Breakthrough Therapy: Pseudomonas fluorescens-Enabled Green Synthesis of pH-Responsive Chitosan–Silver Hybrid Nanoparticles for Next-Generation Pulmonary Drug Delivery Anti-MDR Treatment

by Khulood Fahad Alabbosh, Alaa Elmetwalli, Naseh A. Algehainy and Faisal H. Altemani

Pharmaceutics 2025, 17(12), 1527; https://doi.org/10.3390/pharmaceutics17121527 - 27 Nov 2025

Viewed by 445

Abstract

Background: Multidrug-resistant (MDR) pulmonary infections represent a critical global health challenge, necessitating innovative therapeutic approaches. Green synthesis methodologies offer sustainable alternatives for nanoparticle fabrication while addressing antimicrobial resistance. Methods: Stimuli-responsive chitosan–silver hybrid nanoparticles (CS–Ag HNPs) were biosynthesized using Pseudomonas fluorescens bacterial extracts and loaded with ciprofloxacin for targeted pulmonary delivery. Comprehensive characterization included dynamic light scattering, transmission electron microscopy, UV–visible spectroscopy, and aerodynamic assessment via next-generation impactor. Antimicrobial efficacy was evaluated against MDR Pseudomonas aeruginosa and Klebsiella pneumoniae, including biofilm disruption studies, and biocompatibility was assessed. Molecular docking analysis elucidated binding mechanisms. Cytotoxicity and epithelial barrier integrity were evaluated using Calu-3 cell models. Results: The biosynthesized NPs exhibited optimal physicochemical properties (180 ± 20 nm, PDI 0.21 ± 0.04, ζ-potential + 32.4 ± 3.1 mV) with high encapsulation efficiency (68.2 ± 4.0%). Aerodynamic analysis revealed excellent inhalation characteristics (MMAD 2.6 μm, FPF 65 ± 5%). The hybrid system demonstrated 4-fold enhanced antimicrobial activity against MDR pathogens and significant biofilm disruption (70% for P. aeruginosa, 65% for K. pneumoniae) compared to free ciprofloxacin. Cell viability remained ≥85% at therapeutic concentrations. Molecular docking revealed enhanced drug-target binding affinity (−11.2 vs. −9.3 kcal/mol) and multi-residue interactions. Conclusions: Green-synthesized CS–Ag HNPs represent a promising sustainable platform for combating pulmonary MDR infections through enhanced antimicrobial efficacy and optimal aerodynamic properties. Full article

(This article belongs to the Special Issue Application of Nanomaterials in Pulmonary Drug Delivery)

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20 pages, 3074 KB

Open AccessArticle

The Influence of the External Chemistry of Silica-Based Mesoporous Nanocarriers on Organ Tropism and the Inhibition of Pulmonary Metastases

by Wenping Ye, Yakai Yan, Liuyi Chen, Zhongrui Yang, Guangya Xiang and Yao Lu

Pharmaceutics 2025, 17(11), 1389; https://doi.org/10.3390/pharmaceutics17111389 - 26 Oct 2025

Viewed by 630

Abstract

Background: Mesoporous silica nanoparticles (MS NPs) have attracted significant interest for their role in the advancement of drug delivery systems. However, further investigation is needed to unravel the mechanisms behind the shift in organ tropism that occurs with changes in composition. Methods: To shed light on the correlation between their composition and organ-targeting capabilities, a range of MS NPs was synthesized and subsequently administered intravenously to mice. Results: Our results indicate that MS NPs with a pristine -Si-O-Si- framework, or those incorporating -C-C- or –S-S-S-S- bonds, predominantly accumulated in the liver. The shift to lung tropism was observed exclusively in MS NPs that were enriched with –SH groups. Proteomic analysis identified histidine-rich glycoprotein (HRG) as the most prevalent protein associated with liver-preferred MS NPs in serum, while lung-preferred MS NPs, such as thioether-bridged deformable hollow mesoporous organosilica nanoparticles (HSMONs), showed the highest affinity for albumin. Furthermore, the lung-selective HSMONs, endowed with inherent deformability and glutathione-responsive biodegradability, were utilized as systemic nanocarriers for the delivery of gambogic acid (GA). Conclusions: Leveraging albumin absorbing-triggered tumor cell targeting and trafficking, HSMONs conjugated with GA effectively elicited potent antitumor effects in pulmonary tissue. Full article

(This article belongs to the Special Issue Application of Nanomaterials in Pulmonary Drug Delivery)

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22 pages, 2797 KB

Open AccessArticle

Carbon Dots with Tunable Charge as Mucus-Penetrating Gene Carriers

by Samuel Arca, Clea Witjaksono, Françoise Pons and Luc Lebeau

Pharmaceutics 2025, 17(10), 1330; https://doi.org/10.3390/pharmaceutics17101330 - 14 Oct 2025

Viewed by 794

Abstract

Background/Objectives: Local delivery of gene therapy products through the airways shows great promise for the treatment of a number of serious lung diseases, but its effectiveness is hampered by the mucus layer protecting the lung epithelium in the trachea and bronchi. Methods: To overcome this barrier, we engineered carbon dots (CDs) with mucus penetrating properties. Results: The CDs were synthesized by solvothermal treatment of citric acid and branched polyethyleneimine, and functionalized with maleamic acid groups to create cationic mucoinert nanoparticles with tunable charge. We characterized their interactions with a mucus model through turbidity and transport measurements, and assessed their impact on the viscoelastic properties of the biopolymer. We then demonstrated that the carriers are effective at delivering pDNA to a variety of cell models in vitro. In particular, mucus-producing Calu-3 cells cultured at the air–liquid interface (ALI) were used as a discriminating model to evaluate intracellular delivery of the genetic cargo through a thick layer of mucus at the cell surface. Conclusions: The functionalization of CDs with maleamic acid groups resulted in a 1000- to 10,000-fold increase in transfection efficiency in the mucus-producing model, offering new opportunities for lung gene therapy. Full article

(This article belongs to the Special Issue Application of Nanomaterials in Pulmonary Drug Delivery)

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21 pages, 4509 KB

Open AccessArticle

Sustained-Release Powders Based on Polymer Particles for Pulmonary Delivery of Beclomethasone Dipropionate in the Treatment of Lung Inflammation

by Emanuela Fabiola Craparo, Salvatore Emanuele Drago, Gabriella Costabile, Maria Ferraro, Elisabetta Pace, Roberto Scaffaro, Francesca Ungaro and Gennara Cavallaro

Pharmaceutics 2023, 15(4), 1248; https://doi.org/10.3390/pharmaceutics15041248 - 14 Apr 2023

Cited by 7 | Viewed by 2729

Abstract

Inhaled corticosteroids are the mainstay in the management of lung inflammation associated to chronic lung diseases, such as asthma and chronic obstructive pulmonary disease (COPD). Nonetheless, available inhalation products are mostly short-acting formulations that require frequent administrations and do not always produce the desired anti-inflammatory effects. In this work, the production of inhalable beclomethasone dipropionate (BDP) dry powders based on polymeric particles was attempted. As starting material, the PHEA-g-RhB-g-PLA-g-PEG copolymer was chosen, obtained by grafting 0.6, 2.4 and 3.0 mol%, respectively, of rhodamine (RhB), polylactic acid (PLA) and polyethylene glycol 5000 (PEG) on alpha,beta-poly(N-2-hydroxyethyl)DL-aspartamide (PHEA). The drug was loaded into the polymeric particles (MP) as an inclusion complex (CI) with hydroxypropyl–cyclodextrin (HP-β-Cyd) (at a stoichiometric ratio of 1:1) or as free form. The spray-drying (SD) process to produce MPs was optimized by keeping the polymer concentration (0.6 wt/vol%) constant in the liquid feed and by varying other parameters such as the drug concentration. The theoretical aerodynamic diameter (d_aer) values among the MPs are comparable and potentially suitable for inhalation, as confirmed also through evaluation of the experimental mass median aerodynamic diameter (MMAD_exp). BDP shows a controlled release profile from MPs that is significantly higher (more than tripled) than from Clenil^®. In vitro tests on bronchial epithelial cells (16HBE) and adenocarcinomic human alveolar basal epithelial cells (A549) showed that all the MP samples (empty or drug-loaded) were highly biocompatible. None of the systems used induced apoptosis or necrosis. Moreover, the BDP loaded into the particles (BDP-Micro and CI-Micro) was more efficient than free BDP to counteract the effects of cigarette smoke and LPS on release of IL-6 and IL-8. Full article

(This article belongs to the Special Issue Application of Nanomaterials in Pulmonary Drug Delivery)

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14 pages, 2591 KB

Open AccessArticle

Quality by Design as a Tool in the Optimisation of Nanoparticle Preparation—A Case Study of PLGA Nanoparticles

by Anna-Maria Struzek and Regina Scherließ

Pharmaceutics 2023, 15(2), 617; https://doi.org/10.3390/pharmaceutics15020617 - 12 Feb 2023

Cited by 6 | Viewed by 3837

Abstract

Nanoparticles can be used as drug carriers in various applications (e.g., in pulmonary drug delivery and mucosal vaccination). For further investigations, such as drug release studies, as well as for cell and tissue targeting, particles with defined properties are needed. The purpose of the study was to show a multi-step systematic method utilising quality by design to ensure the quality of ovalbumin loaded polylactic-co-glycolic acid nanoparticles (OVA-PLGA-NP), which can be delivered to the lung, and to gain knowledge of the preparation method (double-emulsion solvent evaporation method) in an early development process. Within a definitive screening design, several process parameters (OVA, PLGA and stabiliser concentrations, stirring time and stirring speed of inner emulsion and stirring time and stirring speed of double emulsion) were varied to analyse their impact on resulting properties (z-average, PDI, loading efficiency and loading capacity). The results showed that the preparation of the inner emulsion mainly influenced the drug loading, while the parameters of the second emulsifying step controlled the size. Then a central composite response surface design was used to achieve a predictable OVA-PLGA-NP with an average particle size of 700 nm and high drug-loading. This also enabled the demonstration of curvature and interaction of the stabiliser and the PLGA concentration. Full article

(This article belongs to the Special Issue Application of Nanomaterials in Pulmonary Drug Delivery)

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20 pages, 33126 KB

Open AccessArticle

Inhalable Polymeric Nanoparticles for Pulmonary Delivery of Antimicrobial Peptide SET-M33: Antibacterial Activity and Toxicity In Vitro and In Vivo

by Laura Cresti, Gemma Conte, Giovanni Cappello, Jlenia Brunetti, Chiara Falciani, Luisa Bracci, Fabiana Quaglia, Francesca Ungaro, Ivana d’Angelo and Alessandro Pini

Pharmaceutics 2023, 15(1), 3; https://doi.org/10.3390/pharmaceutics15010003 - 20 Dec 2022

Cited by 28 | Viewed by 4485

Abstract

Development of inhalable formulations for delivering peptides to the conductive airways and shielding their interactions with airway barriers, thus enhancing peptide/bacteria interactions, is an important part of peptide-based drug development for lung applications. Here, we report the construction of a biocompatible nanosystem where the antimicrobial peptide SET-M33 is encapsulated within polymeric nanoparticles of poly(lactide-co-glycolide) (PLGA) conjugated with polyethylene glycol (PEG). This system was conceived for better delivery of the peptide to the lungs by aerosol. The encapsulated peptide showed prolonged antibacterial activity, due to its controlled release, and much lower toxicity than the free molecule. The peptide-based nanosystem killed Pseudomonas aeruginosa in planktonic and sessile forms in a dose-dependent manner, remaining active up to 72 h after application. The encapsulated peptide showed no cytotoxicity when incubated with human bronchial epithelial cells from healthy individuals and from cystic fibrosis patients, unlike the free peptide, which showed an EC50 of about 22 µM. In vivo acute toxicity studies in experimental animals showed that the peptide nanosystem did not cause any appreciable side effects, and confirmed its ability to mitigate the toxic and lethal effects of free SET-M33. Full article

(This article belongs to the Special Issue Application of Nanomaterials in Pulmonary Drug Delivery)

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Review

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27 pages, 2872 KB

Open AccessReview

Application of Biomimetic SPIONs in Targeted Lung Cancer Therapy: Cell-Membrane Camouflage Technology and Lung Retention Enhancement Strategies

by Quanxing Liu, Li Jiang, Kai Wang, Jigang Dai and Xiaobing Liu

Pharmaceutics 2025, 17(10), 1301; https://doi.org/10.3390/pharmaceutics17101301 - 7 Oct 2025

Viewed by 716

Abstract

Lung cancer remains the leading cause of cancer mortality, hindered by drug resistance, limited targeting, and low immunotherapy response. This review presents biomimetic superparamagnetic iron-oxide nanoparticles (SPIONs) as a next-generation theranostic platform. By cloaking SPIONs with cell membranes—macrophage, neutrophil, or cancer cell—we endow them with biological targeting, immune evasion, and deep lung penetration. Coupled with magnetic field-guided retention and real-time imaging, these systems enable precision hyperthermia, on-demand drug release, and immune microenvironment reprogramming. We critically compare membrane types, outline translational challenges, and propose a regulatory-aligned safety framework. This biomimetic strategy offers a dual diagnostic–therapeutic solution for lung cancer and potentially other solid tumors. Full article

(This article belongs to the Special Issue Application of Nanomaterials in Pulmonary Drug Delivery)

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24 pages, 3656 KB

Open AccessReview

Modified-Release Pulmonary Delivery Systems for Labile Bioactives: Design, Development, and Applications

by Shivani Nana, Mershen Govender and Yahya E. Choonara

Pharmaceutics 2025, 17(4), 470; https://doi.org/10.3390/pharmaceutics17040470 - 3 Apr 2025

Cited by 1 | Viewed by 1380

Abstract

Pulmonary delivery of bioactives has shown to be a promising route for the treatment of respiratory conditions, however, numerous physiological barriers, such as mucociliary clearance and immune responses, pose significant hurdles to treatment efficacy. These barriers specifically affect labile bioactives such as mRNA, peptides, proteins, and probiotics, which are susceptible to degradation due to the prevailing conditions. Various drug delivery platforms have been developed to address these challenges, including, among others, polymeric nanoparticles, micelles, liposomes, and solid lipid nanoparticles that encapsulate and protect the labile bioactives during formulation and administration, enabling improved bioavailability, sustained release, and enhanced formulation stability, while further modification of these platforms allows for targeted drug delivery. This review explores the advanced drug delivery systems that have been designed to protect and release labile active agents in a controlled and targeted manner to the lung, with a specific focus provided on the physiological barriers to effective pulmonary delivery and the formulation considerations to overcome these challenges. The outlook of this pertinent field of study has additionally been provided, highlighting the significant potential of the pulmonary delivery of labile bioactive agents for the prevention and treatment of a variety of respiratory ailments. Full article

(This article belongs to the Special Issue Application of Nanomaterials in Pulmonary Drug Delivery)

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28 pages, 2376 KB

Open AccessReview

The Role of Inhaled Chitosan-Based Nanoparticles in Lung Cancer Therapy

by Allana Carvalho Silva, Mirsiane Pascoal Costa, Thiago Medeiros Zacaron, Kézia Cristine Barbosa Ferreira, Wilson Rodrigues Braz, Rodrigo Luiz Fabri, Frédéric Jean Georges Frézard, Frederico Pittella and Guilherme Diniz Tavares

Pharmaceutics 2024, 16(8), 969; https://doi.org/10.3390/pharmaceutics16080969 - 23 Jul 2024

Cited by 21 | Viewed by 4729

Abstract

Lung cancer is the leading cause of cancer-related mortality worldwide, largely due to the limited efficacy of anticancer drugs, which is primarily attributed to insufficient doses reaching the lungs. Additionally, patients undergoing treatment experience severe systemic adverse effects due to the distribution of anticancer drugs to non-targeted sites. In light of these challenges, there has been a growing interest in pulmonary administration of drugs for the treatment of lung cancer. This route allows drugs to be delivered directly to the lungs, resulting in high local concentrations that can enhance antitumor efficacy while mitigating systemic toxic effects. However, pulmonary administration poses the challenge of overcoming the mechanical, chemical, and immunological defenses of the respiratory tract that prevent the inhaled drug from properly penetrating the lungs. To overcome these drawbacks, the use of nanoparticles in inhaler formulations may be a promising strategy. Nanoparticles can assist in minimizing drug clearance, increasing penetration into the lung epithelium, and enhancing cellular uptake. They can also facilitate increased drug stability, promote controlled drug release, and delivery to target sites, such as the tumor environment. Among them, chitosan-based nanoparticles demonstrate advantages over other polymeric nanocarriers due to their unique biological properties, including antitumor activity and mucoadhesive capacity. These properties have the potential to enhance the efficacy of the drug when administered via the pulmonary route. In view of the above, this paper provides an overview of the research conducted on the delivery of anticancer drug-loaded chitosan-based nanoparticles incorporated into inhaled drug delivery devices for the treatment of lung cancer. Furthermore, the article addresses the use of emerging technologies, such as siRNA (small interfering RNA), in the context of lung cancer therapy. Particularly, recent studies employing chitosan-based nanoparticles for siRNA delivery via the pulmonary route are described. Full article

(This article belongs to the Special Issue Application of Nanomaterials in Pulmonary Drug Delivery)

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31 pages, 1516 KB

Open AccessEditor’s ChoiceReview

State-of-the-Art Review on Inhalable Lipid and Polymer Nanocarriers: Design and Development Perspectives

by Gabriella Costabile, Gemma Conte, Susy Brusco, Pouria Savadi, Agnese Miro, Fabiana Quaglia, Ivana d’Angelo and Francesca Ungaro

Pharmaceutics 2024, 16(3), 347; https://doi.org/10.3390/pharmaceutics16030347 - 1 Mar 2024

Cited by 16 | Viewed by 4274

Abstract

Nowadays, the interest in research towards the local administration of drugs via the inhalation route is growing as it enables the direct targeting of the lung tissue, at the same time reducing systemic side effects. This is of great significance in the era of nucleic acid therapeutics and personalized medicine for the local treatment of severe lung diseases. However, the success of any inhalation therapy is driven by a delicate interplay of factors, such as the physiochemical profile of the payload, formulation, inhalation device, aerodynamic properties, and interaction with the lung fluids. The development of drug delivery systems tailored to the needs of this administration route is central to its success and to revolutionize the treatment of respiratory diseases. With this review, we aim to provide an up-to-date overview of advances in the development of nanoparticulate carriers for drug delivery to the lung tissue, with special regard concerning lipid and polymer-based nanocarriers (NCs). Starting from the biological barriers that the anatomical structure of the lung imposes, and that need to be overcome, the current strategies to achieve efficient lung delivery and the best support for the success of NCs for inhalation are highlighted. Full article

(This article belongs to the Special Issue Application of Nanomaterials in Pulmonary Drug Delivery)

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