Open research questions in Inhalation and Respiratory Drug Delivery

What the literature leaves open

• The study does not provide a comprehensive analysis of the cost-effectiveness of spacer devices. The study is limited to physician perspectives and does not include patient perspectives. The study does not examine the long-term outcomes of spacer device usage.

  Physician perspectives on spacer device usage, prescription patterns, and clinical decision-making factors in the management of respiratory conditions: a nationwide, multicenter cross-sectional observational study · 2026 · DOI

• There is a lack of understanding of physician perspectives on spacer device usage and prescription patterns. There is a need to identify key factors influencing prescription and to examine the role of spacer devices in asthma and COPD management.

  Physician perspectives on spacer device usage, prescription patterns, and clinical decision-making factors in the management of respiratory conditions: a nationwide, multicenter cross-sectional observational study · 2026 · DOI

• The use of phytoceutical-based pulmonary delivery systems represents a promising frontier in the management of pulmonary fibrosis, yet several challenges remain before these innovations can be fully translated into clinical practice. One of the foremost concerns is regulatory approval, as there is a lack of standardized guidelines for evaluating inhalable formulations containing plant-derived compounds. Issues such as dose standardization, product stability, long-term safety, and quality control because phytoceuticals often exhibit variability in their composition depending on plant source, extraction method, and processing. Without strict regulatory frameworks, to ensure it will be difficult reproducibility and patient safety. [63] particularly critical, are Another major challenge lies in the translational potential of these therapies. While preclinical consistently demonstrate antifibrotic, studies antioxidant, and anti-inflammatory effects of phytoceuticals delivered through nanocarriers, there is limited clinical evidence to validate these 112 International Journal of Newgen Research in Pharmacy & Healthcare, June 2026, Vol-4, Issue-1 IJNRPH- 4 (1), 2026 Joshi et al. findings in human populations. The absence of the large, randomized clinical transition from laboratory success to real-world application. Addressing pharmacokinetics, dosing strategies, and long-term efficacy in humans will be essential steps toward clinical acceptance. [62] trials hampers transformative role. Given Looking ahead, personalized medicine approaches the could play a heterogeneity of pulmonary fibrosis, tailoring inhalable phytoceutical formulations based on individual patient profiles—such as genetic predisposition, molecular biomarkers, or disease progression therapeutic outcomes. Integration with advanced drug delivery technologies, nanoparticles responsive to the fibrotic microenvironment, could further refine treatment precision. [63] stage—may including improve smart fibrosis management, In summary, while the concept of phytoceutical- based pulmonary delivery holds great potential to overcoming reshape regulatory barriers, and personalization challenges will be critical to its future success. A multidisciplinary approach involving clinicians, pharmaceutical scientists, and regulatory agencies will be key to advancing this field from experimental promise to clinical reality. translational gaps, CONCLUSION Pulmonary fibrosis remains a devastating condition with limited therapeutic options and high mortality. Conventional therapies such as pirfenidone and nintedanib provide only partial benefits, often accompanied by side effects, high cost, and limited impact on long-term disease progression. In this context, interventions delivered via pulmonary routes are emerging as a novel and complementary strategy. Plant-derived compounds, with their diverse antioxidant, anti- inflammatory, and antifibrotic properties, offer unique opportunities for localized therapy when integrated with advanced delivery platforms such as liposomes, nanoparticles, and micelles. phytoceutical-based

  Translational Insights into Phytoceutical-Based Pulmonary Drug Delivery for Fibrosis Therapy · 2026 · DOI

• The findings of this Special Issue suggest that we are entering an era of intelligent pulmonary delivery. Key themes are likely to shape the research landscape in the years to come. The integration of biomimetic strategies, including the use of nanoparticles coated with cell membranes such as those from macrophages, neutrophils, or cancer cells, holds immense potential for treating lung cancer and severe infections. Implementing Quality by Design principles from the outset is essential for reproducible and scalable production of complex nano-formulations. A systematic understanding of how process parameters such as stirring speed or stabiliser concentration affect nanoparticle size and loading is crucial for achieving clinical success [5]. We expect future studies focused on the systems that are multi-targeted and responsive to stimuli. Releasing a payload only in the presence of specific bacterial enzymes or within the acidic microenvironment of a tumour reduces systemic side effects and increases local efficacy. The development of complex in vitro models, including organ-on-a-chip and advanced air–liquid interface culture, continues to reduce our dependence on animal models, providing accurate data on human lung responses [6]. The editors wish to express their sincere gratitude to the authors for their excellent submissions and to the reviewers for their thorough assessment of these papers. The Special Issue’s success reflects the vibrant and innovative community dedicated to advancing respiratory medicine. The collection offers a valuable resource and promotes further progress in the application of nanomaterials for pulmonary drug delivery. Author Contributions: Conceptualization, I.D. and R.M.; writing—original draft preparation, writing—review and editing, R.M. All authors have read and agreed to the published version of the manuscript. Conflicts of Interest: The authors declare no conflicts of interest.

  Application of Nanomaterials in Pulmonary Drug Delivery · 2026 · DOI

• Computational modeling of lung deposition of inhaled particles in chronic obstructive pulmonary disease (COPD) patients: identification of gaps in knowledge and data.

  Bionic breathing-type airway exposure system for inhalation exposure studies · 2026 · DOI

• Future multicentre controlled designs and longitudinal follow-up are warranted to further evaluate the clinical utility of device-matched PIFR reassessment.

  Changes in device-matched peak inspiratory flow after bedside inhaler coaching and factors associated with residual suboptimal flow: a retrospective observational study · 2026 · DOI

• of and their other because Natural products are widely used in biomedicine, genetic fields engineering, natural biocompatibility, biodegradability, and other intrinsic properties, but their poor bioavailability limits their exploitation. By combining natural products with nanomaterials, new strategies are provided for natural products to utilize their unique advantages, improve their bioavailability, expand the scope of targeted therapies, and take advantage of controlled release. These provide new ideas for the treatment of ALI. In addition, compared with traditional treatment methods, the initial development and preparation costs of NP-NMs are relatively high. However, from the perspective of long-term

  Advances in natural-product-based nanomaterials for treatment of acute lung injury · 2025 · DOI

• Inhalable nano-formulations are very promising as a means of treatment for lung diseases. Compared with traditional formulations, they have many advantages such as increasing solubility, improving bioavailability, and reducing toxicity. However, trans- lational research on inhalable nano-formulations is scarce, and many unresolved issues render industrialization difficult. In this review, we summarized the advantages of nano- formulations for inhalation delivery and the current fundamental research paradigm, from which we found that the fundamental research on nano-formulations was relatively mature, but the translational research lagged far behind. We supposed that the main problem of such a situation was that the pulmonary drug delivery system needed cooperation between the inhalation formulations and the inhalation devices to deliver the drugs effectively. Therefore, we focused on analyzing the influence of inhalation devices on inhalable nano- formulations and what inhalation devices were suitable for inhalable nano-formulations. We believe that vibrating mesh nebulizers, a new-generation nebulizer, are more suitable for inhalable nano-formulations and offered some suggestions for the subsequent optimiza- tion. In addition, for the development of inhalable nano-formulations and their nebulizers, we summarized some of the problems faced. To achieve the goal of large-scale produc- tion, it was necessary to ensure not only the safety of nanomaterials and the optimization Pharmaceutics 2024, 16, 161 16 of 22 of formulations but also the maturity of industrial equipment and the introduction of relevant standards. To date, only one inhaled nano-formulation, ARIKAYCE®, has been approved for marketing by the FDA, and there are a few clinical studies of such formulations. In addition, these studies are focused more on liposomes and less on other nano-formulations. All of this suggests that there are still issues with the translation of inhalable nano-formulations that need to be addressed, in terms of both inhalation devices and formulations. With the advancement in artificial intelligence (AI) technology, we can now monitor quality issues online, together with software analysis, which makes the optimization of the nebulization process easier [90]. We believe that more suitable nebulizers for nano-formulations as novel inhalation devices will appear soon, further promoting the translational research of inhal- able nano-formulations. With the advancement in nanotechnology, more researchers are developing novel inhalable nano-formulations aimed at reducing adverse effects, increas- ing lung deposition rates, and addressing drug resistance [42]. In addition, improving the targeting ability of nano-formulations and overcoming physiological barrier hindrances are also the focus of research on inhalable nano-formulations. In particular, some researchers have proposed the use of microrobots to improve the targeting ability and overcome physiological barriers [164]. We believe that the continuous advancement in these new technologies will further accelerate the development of inhalable nano-formulations and lay the foundation for the industrialization of such formulations. We hope that this review can provide some valuable suggestions for researchers to conduct translational research on inhalable nano-formulations and provide some help for the development of this industry. Lastly, the research and development of inhalable nano-formulations are rising, and we will conduct research in this area in the future. We believe that more inhalable nano-formulations will be marketed in the future to benefit patients with lung diseases. Author Contributions: Conceptualization, X.P. and Z.H.; writing—original draft preparation, S.P. and W.W.; supervision, Z.H.; writing—review and editing, S.P., R.Z. and C.W.; funding acquisition, Z.H. All authors have read and agreed to the published version of the manuscript. Funding: This research was funded by National Natural Science Foundation of China grant number Nos. 82373800 and 82104070, and the Natural Science Foundation of Guangdong Province, under grant No. 2022B1515020085. Institutional Review Board Statement: Not applicable. Informed Consent Statement: Not applicable. Data Availability Statement: Details are available from authors. Conflicts of Interest: The authors declare no conflict of interest.

  Nano-Formulations for Pulmonary Delivery: Past, Present, and Future Perspectives · 2024 · DOI

• Siyuan Peng 1,†, Wenhao Wang 1,†, Rui Zhang 1, Chuanbin Wu 2, Xin Pan 1,* and Zhengwei Huang 2,* 1 School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510275, China; [email protected] (S.P.); [email protected] (W.W.); [email protected] (R.Z.) 2 College of Pharmacy, Jinan University, Guangzhou 510632, China; [email protected] * Correspondence: [email protected] (X.P.); [email protected] (Z.H.) † These authors contributed equally to this work. Abstract: With the development of nanotechnology and confronting the problems of traditional pharmaceutical formulations in treating lung diseases, inhalable nano-formulations have attracted interest. Inhalable nano-formulations for treating lung diseases allow for precise pulmonary drug delivery, overcoming physiological barriers, improving aerosol lung deposition rates, and increasing drug bioavailability. They are expected to solve the difficulties faced in treating lung diseases. However, limited success has been recorded in the industrialization translation of inhalable nano- formulations. Only one relevant product has been approved by the FDA to date, suggesting that there are still many issues to be resolved in the clinical application of inhalable nano-formulations. These systems are characterized by a dependence on inhalation devices, while the adaptability of device formulation is still inconclusive, which is the most important issue impeding translational research. In this review, we categorized various inhalable nano-formulations, summarized the advantages of inhalable nano-formulations over conventional inhalation formulations, and listed the inhalable nano-formulations undergoing clinical studies. We focused on the influence of inhalation devices on nano-formulations and analyzed their adaptability. After extensive analysis of the drug delivery mechanisms, technical processes, and limitations of different inhalation devices, we concluded that vibrating mesh nebulizers might be most suitable for delivering inhalable nano-formulations, and related examples were introduced to validate our view. Finally, we presented the challenges and outlook for future development. We anticipate providing an informative reference for the field. Keywords: inhalable nano-formulations; inhalation devices; industrialization; nebulizers

  Nano-Formulations for Pulmonary Delivery: Past, Present, and Future Perspectives · 2024 · DOI

• The nanoscale structure of mucus is critical for drug penetration, yet remains poorly understood.

  Nanoscale Structural Insights into Human Pulmonary Mucus and Its Snail Slime-Based Surrogate Using Automated TEM Image Processing · 2026 · DOI

• PEGylation is commonly used to improve the pharmacokinetics and efficacy of intravenously administered drug nanocarriers; however its impact on pulmonary drug delivery remains unclear.

  The role of PEGylation in the pulmonary delivery of antifibrotic liposomal therapies · 2025 · DOI

• This review provides a new viewpoint to address these challenges by focusing on the role of swirling flow, a crucial yet under-researched aspect that induces strong turbulence.

  Understanding the role of swirling flow in dry powder inhalers: Implications for design considerations and pulmonary delivery · 2024 · DOI

• Regulatory frameworks for combination products and software as a medical device are evolving but limited. Detailed, DPI-specific guidance on software evaluation remains limited at the EU level. Widespread adoption of digital DPIs is contingent on demonstrating clear benefits in health outcomes, interoperability, and cost-effectiveness.

  Dry Powder Inhalers in the Age of Digital Health: Current Status, Regulatory Considerations and Future Perspectives · 2026 · DOI

• Future research should focus on demonstrating clear benefits of digital DPIs in health outcomes, interoperability, and cost-effectiveness. It should also explore the regulatory challenges related to software qualification and cybersecurity.

  Dry Powder Inhalers in the Age of Digital Health: Current Status, Regulatory Considerations and Future Perspectives · 2026 · DOI

• Current mainstream techniques for manufacturing microporous mesh exhibit inherent limitations. Prior studies have not established a systematic optimization model targeting the ideal particle size range.

  Design study of PSO-ANSYS-based optimization of micromesh atomization particle size and TRIZ-based improvement of oral nebulization mode · 2026 · DOI

• In vivo evaluation of the stent's efficacy and safety. Investigation of the long-term effects of the stent on patient outcomes. Exploration of the use of other hydrophilic modifiers and porous structures.

  Paclitaxel-eluting silicone airway stent with sustained drug release and potent anti-fibrotic activity · 2026 · DOI

• Current airway stenting methods have limitations such as granulation tissue hyperplasia and stent migration. There is a need for a more effective and sustainable treatment option for patients with BCAS.

  Paclitaxel-eluting silicone airway stent with sustained drug release and potent anti-fibrotic activity · 2026 · DOI

• Future research should focus on the development and evaluation of nanoparticulate drug delivery systems for cystic fibrosis therapy. The use of emerging technologies, such as gene therapy and CRISPR-Cas9, may also offer new opportunities for the treatment of cystic fibrosis.

  NANOPARTICULATE DRUG DELIVERY SYSTEMS IN CYSTIC FIBROSIS THERAPY: A COMPREHENSIVE REVIEW OF FORMULATION STRATEGIES, MUCUS PENETRATION MECHANISMS, TARGETED PULMONARY DELIVERY, AND TRANSLATIONAL CHALLENGES · 2026 · DOI

• Conventional therapeutic strategies for cystic fibrosis have several limitations, including poor mucus penetration and systemic side effects. There is a need for innovative approaches to overcome these limitations and improve therapeutic performance.

  NANOPARTICULATE DRUG DELIVERY SYSTEMS IN CYSTIC FIBROSIS THERAPY: A COMPREHENSIVE REVIEW OF FORMULATION STRATEGIES, MUCUS PENETRATION MECHANISMS, TARGETED PULMONARY DELIVERY, AND TRANSLATIONAL CHALLENGES · 2026 · DOI

• However, previous studies on HeliOx efficacy have yielded mixed results, often limited by unrealistic anatomical models and steady-state assumptions, and focus on restricted sections of the airway.

  Transport and deposition of pharmaceutical aerosols in a helium–oxygen mixture in a CT-based nose-to-lung respiratory tract · 2026 · DOI

• Poor water solubility, low bioavailability, and rapid metabolism of Naringin, - Limited cellular uptake and reduced intracellular drug availability of free NAR and uncoated PLGA NP

  Lecithin-Coated PLGA Nanoparticles for Pulmonary Targeting of Naringin: Formulation, Optimization and In Vitro Characterization · 2026 · DOI

• Limited therapeutic options for COPD. Poor water solubility and bioavailability of naringin. Need for effective lung-targeted therapy.

  Lecithin-Coated PLGA Nanoparticles for Pulmonary Targeting of Naringin: Formulation, Optimization and In Vitro Characterization · 2026 · DOI

• The high use of pressurized metered-dose inhalers in France despite their limited effectiveness and high greenhouse gas emissions. The need for educational interventions to increase awareness and intended prescribing of lower-carbon inhaler alternatives.

  Educational Intervention on Environmentally Responsible Inhaler Prescribing Among French General Practitioners: Pilot Pre-Post Study · 2026 · DOI

• There is a need for in vitro platforms that reflect key exposure and mechanical features of the alveolar environment. The study aims to address the gap in understanding the effects of physiological strain on lung epithelial cells by exposure to aerosolised quartz silica.

  Impact of physiological strain on lung epithelial cells by exposure to aerosolised quartz silica in a perfused bioreactor · 2026 · DOI

• Further research is needed to overcome the physical, biological, and technical barriers that must be overcome to successfully deliver biologics to the lung. The development of inhaled biologics for the treatment of respiratory diseases requires careful consideration of physicochemical, physiological, pharmacological, and commercial challenges. The paper suggests that mRNA represents a promising approach for restoring sufficient CFTR expression in the lungs.

  Developmental Progress and Future Potential for Inhaled Biologics in the Treatment of Respiratory Diseases · 2026 · DOI

Most-cited papers in Inhalation and Respiratory Drug Delivery

• Nanotoxicology: An Emerging Discipline Evolving from Studies of Ultrafine Particles · Environmental Health Perspectives · 2005 · 6,470 citations
• Ultrafine Particles Cross Cellular Membranes by Nonphagocytic Mechanisms in Lungs and in Cultured Cells · Environmental Health Perspectives · 2005 · 1,166 citations
• INCIDENCE AND SEVERITY OF ANAPHYLACTOID REACTIONS TO COLLOID VOLUME SUBSTITUTES · The Lancet · 1977 · 1,044 citations
• Polyethylene Glycol Immunogenicity: Theoretical, Clinical, and Practical Aspects of Anti-Polyethylene Glycol Antibodies · ACS Nano · 2021 · 569 citations
• Instillation of Six Different Ultrafine Carbon Particles Indicates a Surface Area Threshold Dose for Acute Lung Inflammation in Mice · Environmental Health Perspectives · 2005 · 386 citations
• Ultrafine Particles in the Urban Air: To the Respiratory Tract--And Beyond? · Environmental Health Perspectives · 2002 · 290 citations
• Ultrafine particle deposition in subjects with asthma. · Environmental Health Perspectives · 2004 · 282 citations
• Efficient Elimination of Inhaled Nanoparticles from the Alveolar Region: Evidence for Interstitial Uptake and Subsequent Reentrainment onto Airways Epithelium · Environmental Health Perspectives · 2007 · 251 citations
• In Search of the Most Relevant Parameter for Quantifying Lung Inflammatory Response to Nanoparticle Exposure: Particle Number, Surface Area, or What? · Environmental Health Perspectives · 2006 · 227 citations
• Systemic Microvascular Dysfunction and Inflammation after Pulmonary Particulate Matter Exposure · Environmental Health Perspectives · 2005 · 215 citations

Most recent work

• Rationalizing nose-to-brain drug delivery: Machine learning-guided optimization and mechanistic elucidation of olfactory deposition for nasal sprays · Journal of Controlled Release · 2026
• Liposomal particokinetics and intratumoral microdistribution: A quantitative reassessment of the enhanced permeability and retention effect · Journal of Controlled Release · 2026
• Inhalation-Based Nanoparticle Drug Delivery Targeting the Diseased Lower Airways in Idiopathic Pulmonary Fibrosis · Pharmaceutics · 2026
• Terpene-Enriched Nitazoxanide-Loaded Chondrosomes: Aerodynamic Characterization and In Silico Evaluation of Antiviral Activity · Pharmaceuticals · 2026
• In silico high-resolution whole lung model to predict the locally delivered dose of inhaled drugs · Communications Medicine · 2026
• Breathing lung-on-chip: a versatile tool for assessing respiratory toxicity across multiple therapeutic modalities · Archives of Toxicology · 2026
• Human lung parenchyma: tensile mechanics and the effects of smoking · Journal of The Royal Society Interface · 2026
• Morphology-driven zinc oxide biointeractive carriers with biological barrier modulating effects for pulmonary delivery of liraglutide · Journal of Nanobiotechnology · 2026
• Inhaled formulations for bacterial pneumonia: Strategies and advances in drug delivery · Bioactive Materials · 2026
• Repeated pulmonary dosing of β-glucan-chitosan-PLGA nanoparticles controls Mycobacterium tuberculosis in mice · Antimicrobial Agents and Chemotherapy · 2026

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