Inhalation: A Smart Strategy and Increasing Potential for Drug Delivery

Abstract

The delivery of inhaled drugs is a critical and evolving strategy in modern medicine that offers distinct advantages over other routes of administration. Compared to traditional methods such as oral, intravenous, or transdermal delivery, inhalation provides rapid onset, high local drug concentrations, reduced systemic side-effects, and improved patient compliance. In addition to its established use for the treatment of respiratory diseases, such as asthma and chronic obstructive pulmonary disease (COPD), recent technological advancements have expanded its application in systemic therapies, vaccines, and biologics. Innovative devices like dry powder inhalers, soft mist inhalers, and smart inhalers, integrated with digital health technologies, enable precise dosing, adherence monitoring, and potential personalization of therapy. Emerging trends, such as inhaled nanoparticles, gene and RNA therapies, and inhaled vaccines, have redefined the landscape of inhalation drug delivery. Despite these advances, challenges remain in terms of formulation stability, device compatibility, interpatient variability, and environmental concerns related to propellants. Future research should emphasize green technologies, integration with telehealth, patient-specific inhaler matching, and broader therapeutic applications beyond pulmonary diseases. As device engineering, digital health, and biopharmaceutical research converge, inhalation therapy has become an essential component of precision and patient-centric medicine, providing new avenues for disease treatment and prevention under both local and systemic conditions.

Routes of Drug Administration

Drug delivery is critical for disease therapy and prevention because it is closely associated with drug safety and effectiveness. Therefore, a correct and precise choice of drug delivery is required for patients. Currently, the major drug delivery systems include topical cream/emulsion/ointment/gel, transdermal patches, oral administration, intravenous (IV) injection, intramuscular (IM) injection, subcutaneous (SC) injection, microneedles, and inhalation. A comparison of the various drug delivery systems is presented in Table 1 and Figures 1 and 2.

Table 1.

Comparison of Major Delivery Systems

Delivery	Topical Cream	Transdermal Patch	Oral	Intravenous	Intramuscular	Subcutaneous	Microneedle	Inhalation
Description	A cream to be smeared on the skin	An adhesive patch to be placed on the skin	Uptake of drugs by swallowing or drinking through mouth	An injection into a vein and directly into the bloodstream	An injection deep into the muscle to allow the bloodstream to absorb quickly	An injection given just on the subcutaneous tissues of skins	Micro-size needles are aligned on the surface of a small patch	Uptake of drugs by inhaler through mouths or noses
Mechanism of delivery	Drugs permeate through skin pores	Drugs permeate stratum corneum barrier and diffuse across the skin	Drugs enter the body through digestive tracts and spread through the blood stream	Drugs are placed directly in the vein and spread through the blood stream	Drugs placed directly in the muscle and spread through the blood stream	Drugs are placed directly in the dermis and spread through the blood stream	Drugs bypass stratum corneum and are placed directly in the epidermis or dermis	Drugs enter the body through respiratory tracts and spread through the blood stream
Action	Local	Local	Systemic	Systemic	Systemic	Systemic	Systemic	Local or systemic
Onset	Slow	Slow	Slow	Fast	Fast	Fast	Fast	Fast
Pain	No	No	No	Yes	Yes	Yes	No	No
Bioavailability	Poor	Insufficient	Insufficient	Sufficient	Sufficient	Sufficient	Sufficient	Sufficient
Self-administration	Yes	Yes	Yes	No	Possible	No	Yes	Yes
Reference	[1, 2]	[3, 4]	[5, 6]	[7, 8]	[9, 10]	[11, 12]	[13, 14]	[15, 16]

Figure 1.

Comparison of drugs delivered by topical cream, transdermal patch, intravenous injection, intramuscular injection, subcutaneous injection, and microneedles.

Figure 2.

Different from oral administration, where drugs are taken into the digestive system by swallowing or drinking, inhalation administration means that drugs are delivered to the respiratory system through nostrils or mouths using inhalers.

The choice of drug administration route is complex and dependent on drug characteristics, patient traits, and disease types, as follows:17–20 (1) Drug nature: Chemical properties (eg, easily broken down by stomach acid or digestive enzymes), fat-soluble or water-soluble, molecular size and structure, and sensitivity to heat, light, or oxygen. (2) Drug action: Sites of action (eg, systemic like blood pressure medication or topically like eye drops or skin ointments), required release rate (eg, rapid onset of action like a pain reliever or long-acting sustained release like a chronic disease), and accessibility of target cells or organs (eg, some areas like the blood–brain barrier require special designs for penetration). (3) Patient compliance: Age and physical condition (eg, infants or the elderly are not suitable for injections or swallowing large pills), acceptability (eg, some patients do not like injections and prefer oral or inhaled medications), and convenience (eg, complex dosage forms may reduce patients’ willingness to continue taking medication when providing home care). (4) Pharmacokinetics: Absorption (eg, some drugs are poorly absorbed orally and need to be administered by injection or other routes), distribution (eg, drugs will be effectively distributed to the site of action), metabolism (eg, oral administration may have a strong first-pass effect to reduce the effective concentration), and elimination (eg, some drugs may be easily and rapidly degraded in the liver and eliminated in the kidneys).

Why Inhalation Drugs are Important

Inhalation drugs offer several unique advantages for treating specific medical conditions, especially those related to the lungs and the respiratory system. Drugs commonly administered via inhalation include bronchodilators (eg, salbutamol and formoterol), corticosteroids (eg, fluticasone and budesonide), antibiotics (eg, tobramycin for cystic fibrosis), insulin (eg, Technosphere insulin-Afrezza ®), and pain medications (under research for systemic delivery). The following are the main reasons and examples to show that drug inhalation is important.

Direct Delivery to the Lungs

The rapid onset of action of inhaled medications is primarily attributable to the unique anatomy and physiology of the lungs. The human lungs contain an extensive network of branching airways that terminate in millions of alveoli, providing a large surface area for gas and drug exchange. The alveolar epithelium is extremely thin and lies in close proximity to a dense pulmonary capillary network, enabling rapid diffusion of inhaled drugs into the bloodstream. In addition, the lungs receive the entire cardiac output, ensuring efficient systemic absorption. These anatomical and physiological features allow inhaled drugs to reach their target site—the bronchial tree and alveoli—quickly, making this route particularly effective in emergency situations such as acute asthma attacks.

Asthma is a common chronic inflammatory disease of the airways and remains a major cause of morbidity and mortality among children and young people. The disease is characterized by airway inflammation, bronchial hyperresponsiveness, smooth muscle constriction, mucosal edema, and increased mucus production, all of which narrow the airways and increase airflow resistance. Following an asthma attack, there is an important opportunity to prevent future exacerbations by evaluating treatment adherence and optimizing long-term asthma control.21 Careful identification of asthma triggers, anatomical and functional factors contributing to airway obstruction, barriers related to health beliefs, and socioeconomic influences is essential, as these factors may have contributed to the exacerbation.21 Most children with asthma experience significant symptom relief with low-dose inhaled corticosteroids, which act locally on the airway mucosa to reduce inflammation while minimizing systemic exposure.21 Although symptoms may not always appear severe at presentation, patients with acute asthma attacks frequently require emergency department management due to significant impairment of respiratory function. Early functional assessment should focus on vital signs, respiratory rate, oxygen saturation, and the degree of perceived dyspnea.22 From a physiological perspective, airflow limitation during an asthma attack can lead to air trapping and dynamic pulmonary hyperinflation, which increase the work of breathing and compromise ventilatory mechanics. When these changes progress, immediate intervention is required. Prompt delivery of inhaled bronchodilators directly to the airways and, when necessary, intravenous therapy should be initiated to treat refractory symptoms and prevent further deterioration of respiratory function.22

Effective for Respiratory Diseases

Inhalation is ideal for respiratory conditions, because it delivers the drug directly to the site of action. Therefore, inhalation is the first-line delivery method for many respiratory diseases related to the lungs, such as asthma, chronic obstructive pulmonary disease (COPD), cystic fibrosis, and pulmonary infections, including coronavirus infectious disease 2019 (COVID-19).

The worse outcomes of COPD may result from decreased adherence and increase the risk of disease exacerbation, and long-term mortality. Factors that may influence adherence are related to patients, clinicians, and the healthcare system.23 Among the clinician factors, it is crucial to deliver simplified treatment regimens using an inhaler adapted to the patient.23 Smart inhalers and simplified treatment regimens can effectively improve adherence and long-term outcomes in COPD.23

Lung infection by bacteria such as Pseudomonas aeruginosa is the most important cause of death in cystic fibrosis; therefore, antimicrobial therapy is a major strategy for the management of microbial infections.24 The major and effective control approaches for patients with cystic fibrosis include rigorous microbiological surveillance, intensive eradication therapy, and long-term maintenance therapy based on inhaled antibiotics.24

The development of COVID-19 treatment is still needed to improve outcomes, although global approval and distribution of vaccination programs have significantly prevented infection with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). In the early pandemic period, patients with pre-existing asthma or COPD were under-represented among those with COVID-19.25 Inhaled corticosteroids routinely taken by patients with asthma and COPD could effectively protect against severe COVID-19 in clinical studies, indicating that it may be a potential treatment for COVID-19.25

Lower Dosage Requirements

Because of the targeted delivery, the required inhalation drug dose is usually lower than that of other traditional routes, such as oral administration or injection. They are transmitted directly to the lungs to have a higher local concentration so that the treatment is effective at lower doses compared to systemic administration, thus minimizing drug waste.

Local pulmonary delivery of biopharmaceuticals may provide some advantages for the treatment of lung diseases, such as the rapid onset of action, reduced systemic exposure, needleless administration, and particularly lower dose requirements.26 However, it is challenging to formulate a protein for inhaled delivery and requires proteins with favorable biophysical properties to adapt to the forces related to the formulation, delivery, and inhalation devices.26 Nanobodies derived from naturally occurring heavy-chain-only immunoglobulins are highly soluble, stable, and exhibit biophysical characteristics suitable for pulmonary delivery well.26 Nanobodies have been shown to be delivered via the pulmonary route, and it is advantageous to use them for inhaled delivery to the lung; for example, a nanobody (ALX-0171) could be used for the effective treatment of respiratory syncytial virus (RSV) infections at very low doses in clinical development.26

Reduced Systemic Side-Effects

Inhalation drugs usually act on target organs, minimizing drug exposure to the rest of the body and thus reducing systemic side-effects. Their systemic side-effects are lower because fewer drugs circulate in the bloodstream than via oral or injectable routes.

Systemic administration of cytotoxic chemotherapy for cancer therapy administered intravenously and orally is known to cause severe and debilitating systemic side-effects. Regional therapy with cytotoxic agents potentially reduces the extent of drug exposure and risk of systemic side-effects.27 Inhaled cytotoxic chemotherapy can be used as an effective regional therapy for both primary lung cancer and lung metastases from other primary tumors to avoid the side-effects of systemic therapy.27 Moreover, some aerosol chemotherapeutic agents are absorbed directly into arterial circulation, showing therapeutic effects at extrapulmonary sites.27 Currently, aerosol administration of several different chemotherapeutic agents is still being evaluated either in preclinical settings or in early phase human trials.27 Some studies have indicated that inhaled chemotherapy is feasible and effective for treating lung tumors with reduced systemic side-effects.27

Non-Invasive and Convenient

Inhalation drugs via oral, pulmonary, and nasal delivery using inhalers and nebulizers are easy to use at home. It is suitable for the long-term treatment of patients with chronic diseases for convenience and to avoid the discomfort caused by injections.

The potency and specificity of biologics make them more important drugs than conventional chemical drugs for the treatment of certain diseases. However, it is difficult to administer biologics noninvasively because of their intrinsic characteristics such as high molecular weight, hydrophilicity, and instability.28 In particular, long-term administration is required when biologics are used to treat chronic disorders. Consequently, researches made many efforts to develop a formulation for non-invasive administration routes for the improvement of patient compliance and convenience for use at home.28 Strategies for non-invasive delivery, including oral, pulmonary, and nasal delivery, have recently been discussed and evaluated.28 Insulin, calcitonin, and heparin are the three main targets of discussion because they represent proteins, polypeptides, and polysaccharide drugs, respectively.28

Potential for Systemic Delivery

Some inhalation drugs are designed for systemic effects based on the large surface area of the lungs and the blood supply, such as inhalable insulins (eg, Afrezza), pain medications, vaccines, lung cancer therapeutics, and drugs for gene therapy.

The administration of repurposed non-oncology drugs loaded in nanocarriers through inhalation may act as an alternative strategy for the treatment of lung cancer, owing to the insufficiency of first-line chemotherapeutics, the presence of resistant tumors, and inappropriate routes of administration.29 Site-specific release using a suitable inhalation device may provide enhanced efficacy, reduce mortality, and improve the quality of life of patients.29

Mouse cytomegalovirus (MCMV) has been used as an intranasal and injectable gene therapy system to successfully extend the lifespan of animals.30 Glucose tolerance and physical performance were specifically improved, with no loss of body mass or alopecia.30 Intranasal and injectable preparations would deliver gene therapy to multiple organs safely and efficiently, having long-term persistence advantages, and without carcinogenicity or side-effects.30

Type of Inhalation

Inhalation drug delivery systems are categorized based on the device used and form of the drug (gas, mist, powder, etc). Inhalation is generally classified into the following categories: nasal inhalation (through the nose), oral/pulmonary inhalation (through the mouth into the lungs), steam inhalation (through the nose and/or mouth), and volatile anesthetic inhalation (through an anesthetic mask). Among these, nasal and oral inhalation are the main routes of drug administration.

Nasal inhalation is a method of administering medications directly into the respiratory tract, including the lungs, through the nostrils. This novel approach is used for the treatment of both local and systemic of diseases, particularly those affecting the lungs like asthma, COPD, and cystic fibrosis. Additionally, nasal inhalation vaccines have been used to prevent diseases caused by respiratory pathogens such as SARS-CoV-2,31,32 influenza virus,33 RSV,34 and Mycobacterium tuberculosis.35 Inhalation has been extensively used for drug delivery and has increasing potential for the therapy and prevention of diseases (Table 2).

Table 2.

Comparison of Nasal Inhalation and Oral Inhalation

Aspect	Nasal Inhalation	Oral Inhalation
Entry route	Nostril	Mouth
Primary target site	Nasal mucosa	Lungs (alveoli, bronchi)
Onset of action	Fast, especially for local or CNS effects	Fast, especially for bronchodilators and systemic drugs
Absorption site	Nasal epithelium, olfactory region	Alveolar-capillary membrane
Systemic delivery	Possible (eg, desmopressin, naloxone)	Common for asthma, COPD drugs, insulin, etc.
Local delivery use	Allergic rhinitis, nasal congestion	Asthma, COPD, cystic fibrosis
Bypasses first-pass metabolism	Yes	No
Drug form example	Spray, drop, gel	pMDI, DPI, nebulizer
Device	Nasal spray/delivery pump	Inhalers (MDI, DPI), nebulizer
Volume administered	Small (25–200 µL per nostril)	Variable (depend on formulations and devices)
Patient coordination required	Low	Moderate to High (especially with MDI)
Bioavailability variability	Moderate, depends on mucociliary clearance, congestion	High, depends on inhalation technique, lung deposition
Irritation potential	Possible (eg, nasal dryness, stinging)	Possible (eg, throat irritation, cough)
CNS drug access	Potential for nose-to-brain delivery	Limited (unless be systemically absorbed)
Limitations	Nasal pathology, congestion affects delivery	Requires proper technique; less effective in acute distress
Drug examples	Oxymetazoline, naloxone, desmopressin, COVID-19 vaccine (iNCOVACC®)36	Salbutamol, fluticasone, tiotropium, insulin, COVID-19 vaccine (Convidecia Air®)36
References	[37–41]	[42–46]

Abbreviations: CNS, central nervous system; COPD, chronic obstructive pulmonary disease; pMDI, pressurized metered dose inhaler; DPI, dry powder inhaler.

Oral inhalation is a drug delivery system consisting of a device and a corresponding formulation, in which drugs are taken through the mouth as a fine mist given by an inhaler. Large droplets would only prime the mouth and throat, but small droplets may be transmitted further throughout the body. The drug formulation must be designed to be consistent with the device because they must work together to achieve the intended drug effects in patients.47 Oral inhalation drugs are usually classified into three types: pressurized metered-dose inhalers (pMDIs or MDIs), dry powder inhalers (DPIs), and nebulizers. Oral inhalation provides the possibility of targeting drugs locally to different areas of the respiratory tract or delivering them systemically using the larger surface areas of the alveoli, such as in systemic conditions (eg, diabetes and pain management) in some special therapies. Pulmozymes and inhaled insulins (eg, Exubera and Afrezza) are examples of successful pulmonary drug delivery for commercial use.45 Although the subsequent over-reactions (eg, unproven fear of lung cancer) of Exubera may hinder the development of systemically inhalable protein and peptide drugs, many inhalable biopharmaceuticals have recently advanced to clinical trials.45 Oral inhalable products have become possible alternatives for the delivery of small molecules, avoiding oral pharmacokinetics and/or liver first-pass effects.45 The development of novel inhalation devices and more studies on lung physiology will promote the oral inhalation of drugs to be an attractive therapeutic strategy (Table 2).

Devices Used for Inhalation

The devices utilized for the administration of inhaled drugs are very crucial in the management of obstructive lung diseases, such as asthma and COPD. They should deliver a high proportion of fine particles, be easy to use, and offer consistent and accurate doses of the active substance to make sure a high bronchial deposition of inhaled drugs. Currently, four types of inhalers are extensively used including nebulizers, dry powder inhalers (DPIs), pressurized metered-dose inhalers (pMDIs), and soft mist inhalers (SMIs) (Table 3).

Table 3.

Types of Inhalation Devices

Device	Characteristic
Nebulizer:	Convert liquid medications into mist, useful for infants, elderly, or those with difficulty
Dry Powder Inhaler (DPI)	Breath-activated devices delivering powdered medication
Pressurized Metered-Dose Inhaler (pMDI)	Pressurized canisters delivering a specific dose per puff
Soft Mist Inhalers (SMI)	Deliver a slow-moving mist to improve lung deposition

Nebulizers are used by patients who cannot use other inhalers; however, they require a long administration time and are unable to ensure precise dosages. The two most common types are jet nebulizers and vibrating-mesh nebulizers. Vibrating-mesh nebulizers perform well; however, jet nebulizers are the most commonly used. Nebulizer type should be decided after seriously considering the needs of the drug combination, diseases, patient types, target sites for deposition, healthcare professionals, and patient safety.48 Although we may focus on other delivery devices, such as pMDIs and DPIs, nebulizers are still considered a viable and common approach for respiratory drug delivery because of the easy formulation of many drugs in water and their delivery as aqueous aerosols.49 For example, in COPD treatment, pMDIs, DPIs, and SMIs may be appropriate for most patients with COPD; however, these devices may not be suitable for these devices.50 Fortunately, nebulizers can provide these patients with an alternative administration route to avoid the requirement of inspiratory flow, manual dexterity, or complicate harmonization between hands and breath.50

DPIs are micronized drug particles attached to larger lactose carrier particles. Different DPI formulations have been developed to overcome the challenges of aerosolizing fine cohesive drug-containing particles for the development of consistent and effective DPI products.51 Particle engineering processes can produce micron-sized drug-containing particles and their subsequent assembly into carrier-based or carrier-free components.51 Although patients should produce an adequate inspiratory flow to extract drugs and disaggregate drugs from the carriers, it is not required to have harmonization between actuation and inhalation. Recent advances in DPIs include nanoparticle systems, siRNA-based medications, liposomes, and delivery systems based on proliposomes.52 For example, silver nanoparticle-based DPIs have revealed significant outcomes in the infected lungs of COVID-19 patients.53

pMDIs have been used as first-line treatment for pulmonary conditions since the 1950s. The development of therapies based on pMDIs will continue because of the expanding applications of pMDIs beyond asthma and COPD.54 The pMDIs have become popular because they are small, cheap, rapid, and quiet. Their performance is improved by spacers and their delivery speed is reduced by new technologies.55 Factors such as formulation variables on metrics controlling the performance of pMDIs can potentially benefit patients by providing improved drugs for current indications to initiate new areas of therapy.55

SMIs are medications dissolved in an aqueous solution without propellants and are dispensed as slow aerosol clouds resulting from the energy of a spring.56 They can be used as reusable devices to reduce the environmental impact of inhalers and are more convenient for patients because they are propellant-free.57 By the power of SMIs, single or multiple doses of inhalable drug aerosols in the form of slow mist are delivered to patients.58 SMIs provide a longer and slower release of aerosols with a smaller ballistic effect than traditional inhalers, resulting in a limited loss in the oropharyngeal area.58 Therefore, patients do not require much coordination between actuation and inhalation. Smart inhalers connected to smartphones are promising for supplementing information associated with patient adherence and inhaler techniques.58

Currently, innovative inhalation devices are used clinically, and their benefits are summarized in Table 4.

Table 4.

Technological Innovations for Inhalation Devices

Device	Benefit	Example
Dry Powder Inhaler (DPI)	Breath-actuated, no propellant requirement	Ellipta®59,60
Pressurized Metered-Dose Inhaler (pMDI) with Smart Dose Counters	Prevention of under-/over-dosing	Digihaler61,62
Soft Mist Inhalers (SMI)	Lower inspiratory effort	Respimat®56,63

Emerging Trends

The delivery of inhalation drugs has long been central to the treatment of respiratory diseases such as asthma and COPD. However, recent innovations have expanded their use beyond pulmonary disorders, opening doors to systemic therapies and precision medicine. Current applications include the treatment of respiratory diseases (eg, asthma, COPD, and cystic fibrosis), systemic diseases (eg, diabetes and pain management), pulmonary infections (eg, inhaled antibiotics for Pseudomonas aeruginosa and tuberculosis), and disease prevention (eg, COVID-19 vaccine). The emerging trends in the development and application of inhalational drugs based on various strategies are discussed below.

Smart Inhaler Technology

A smart inhaler integrates connectivity with a mobile phone application via Bluetooth. It is built using sensor technology that can record the time and location for each use. The first smart inhaler approved by the US Food and Drug Administration (FDA) was Teva’s ProAir Digihaler (albuterol sulfate), with a use-tracking real-time sensor synchronized with a mobile app.64 These sensors may be an integral part of the inhaler or an external device attached to the primary inhaler. This device could be used to establish an automatic reminder for the next dose. Smart inhalers can help doctors and patients track conditions and monitor the efficacy of treatment over time, without the need to keep diaries or written records. By setting related notifications, smart inhaler technology is a useful tool for optimizing treatment schedules, dosage reminders, and tracking usage., This will allow both patients and doctors to know how, why, where, and when the symptoms improve or worsen (Table 5). Below are examples of asthma treatment using smart inhalers.

Table 5.

Summary of Innovative Strategies for the Development of Inhalation Drugs

Innovative Strategy	Tendency
Smart inhaler technology	Digital inhalers with sensors for dose tracking and adherence monitoring
	Devices with sensors for tracking usage and ensuring adherence
	Bluetooth-enabled devices to synchronously with Apps for remote patient management
	Artificial intelligence (AI) integration for predictive maintenance of inhalation therapy in chronic diseases
Inhaled biologics	Inhaled biologics are biologic drugs delivered directly to the lungs via an inhaler, providing advantages such as rapid absorption due to the lung’s large surface area
	Peptides, proteins, and antibodies are being reformulated for pulmonary delivery
Nanoparticles and liposomal formulations	Improvement of drug stability and absorption
	Nanocarriers allow for sustained release and targeting of specific lung tissues
Gene, RNA and target therapies	Pulmonary delivery of siRNA, mRNA, and CRISPR-Cas components
	Target lung diseases under exploration like cystic fibrosis, lung cancer, pulmonary hypertension and COVID-19
Inhaled vaccines	Needle-free, mucosal immunity-inducing formulations
	Induction of triple immunity, including humoral, cellular, and mucosal immunity
	Interception of pathogens at the first line when they invade
	Dosage sparing effect
	COVID-19 expedite research into inhaled mRNA and adenovirus-based vaccines
Personalized inhalation therapy	Drugs and their inhalers must be specifically designed to suit specific patient’s needs
	Pharmacogenomics and AI algorithms help customize treatment regimens.
	Patient-specific inhaler-device should be matched based on inspiratory flow profile

A smart inhaler via Bluetooth has the potential to improve patient adherence to asthma therapies and maintain their condition under control. The devices need to be designed with health systems and patients in mind so that they can provide the maximum benefit.65

Smart spacers can monitor inhaler techniques to enhance adherence to inhaled medications and achieve better outcomes. A definitive randomized controlled trial revealed that it was feasible for smart spacer-driven education in patients with asthma to reduce inhaler errors in a short-term study.66 However, it is necessary to assess the clinical effects in long-term and larger studies.66

Inhaled Biologics

Inhaled biologics (eg, peptides, proteins, enzyme and genes) are being reformulated for the pulmonary delivery of drugs delivered directly to the lungs via an inhaler to avoid gastrointestinal degradation and provide targeted delivery. The advantages of this non-invasive route include improved patient compliance, rapid onset of action, and direct access, preferably for therapy and prevention of respiratory diseases. Inhaled biologics provide benefits such as rapid absorption owing to the large surface area of the lungs (Table 5). Below are examples of treatments for COVID-19 and lung cancer using inhaled biologics.

The efficacy of first-generation COVID-19 vaccines is decreasing, and frequent breakthrough infections have facilitated the transmission and evolution of SARS-CoV-2. Some immunocompromised patients cannot be protected by COVID-19 vaccines and are still vulnerable to severe disease, although they have received three primary-dose vaccines and heterologous boosters. The evolution of new SARS-CoV-2 variants has also weakened the therapeutic efficacy of monoclonal antibodies.67 Fortunately, inhalation treatment with angiotensin-converting enzyme 2 (ACE2) receptor has decreased the severity of COVID-19 in animal models,68 and budesonide inhalation may be effective in randomized controlled trials.69

Aerosolized IgG accumulated in the lungs and tumor and aerosolized cetuximab also restricted mouse tumor growth. Although the administration of anticancer mAbs via the airways deserves further evaluation for the clinical treatment of lung cancer, it is potentially effective and may limit systemic side-effects.70 An immunotherapeutic chitosan-antibody complex inhaled through non-invasive aerosol inhalation was developed for immunotherapy against lung cancer in mice.71 Therefore, it is promising for immunotherapy against lung metastasis using a unique aerosol inhalation delivery system for immune checkpoint blockade antibodies, without the concern of systemic toxicity.71 Additionally, an inhaled aerosolized immunotherapeutic DV281 (C-class CpG-ODN) combined with an inhibitor of the anti-programmed cell death protein 1 (PD-1) immune checkpoint was used to treat lung cancer.72

However, challenges for inhaled biologics exist in the maintenance of drug stability, manufacture of specialized formulations, and overcoming anatomical barriers within the lungs (1) Maintenance of drug stability is difficult:73 Biologics such as proteins, peptides, and nucleic acids are highly sensitive to physical and chemical stress. During aerosolization, shear forces, air–liquid interfaces, and exposure to heat or moisture can induce denaturation, aggregation, or loss of biological activity. Long-term storage also poses problems, as many biologics require strict control of temperature and humidity to prevent degradation. (2) Manufacture of specialized formulations for inhalation is technically demanding:74 Biologics must be formulated into particles with precise aerodynamic diameters (typically 1–5 μm) to ensure deep lung deposition, while preserving molecular integrity. Processes such as spray drying, freeze drying, or jet milling can compromise protein structure or reduce yield. In addition, excipient selection is limited, as additives must be both biocompatible with the lung and capable of stabilizing the biologic during processing and delivery. (3) Anatomical and physiological barriers within the lungs significantly limit effective delivery:75 Mucus layers, pulmonary surfactants, and alveolar macrophages can trap or clear inhaled biologics before they reach target cells. Enzymatic activity in the lung may further degrade sensitive molecules, and non-uniform airflow can lead to inconsistent regional deposition. Overcoming these barriers remains a major hurdle for successful inhaled biologic therapies.

Nanoparticles and Liposomal Formulations

The inhalable liposomal nanoparticles loaded with antibiotics are an effective method for the treatment of lower respiratory tract infections such as cystic fibrosis, COPD, and bronchiectasis. They have shown significantly higher antibacterial efficacy, and that inhaled antibiotics demonstrate sustained enhancement in lung function in both preclinical and clinical settings are clear76 (Table 5). Below are examples of the treatment of Pseudomonas aeruginosa and Mycobacterium avium infections using nanoparticles and liposomal formulations.

Arikace™, a novel formulation of inhaled liposomal amikacin, is an effective therapeutic agent for cystic fibrosis pulmonary infections, because it can penetrate deep within airway secretions and Pseudomonas aeruginosa biofilms.77 Moreover, inhaled liposomal amikacin has been applied in the treatment of pulmonary infections which are difficult to treat.77

The efficacy and safety of an amikacin liposome inhalation suspension (ALIS) was evaluated in patients with refractory Mycobacterium avium complex (MAC) lung disease.78 Compared to guideline-based therapy alone, addition of ALIS to standard guideline-based therapy in treating refractory MAC lung disease had greater sputum culture conversion by month 6, and adverse events related to ALIS were generally mild to moderate.78 A liposomal amikacin inhalation suspension (Arikayce) indicated for MAC lung disease was approved by the US FDA in 2019.79

RNA and Target Therapies

The rapidly growing number of studies on RNA therapeutics for pulmonary diseases and the development of inhaled drugs have facilitated the direct delivery of RNA therapeutics to the target site of the lung to minimize systemic exposure.80 Furthermore, inhaled gene therapy targeting lung diseases has recently attracted increasing interest, and preclinical research is ongoing, although no products have been successfully approved in the market yet81 (Table 5). Below are examples of the treatment of lung diseases using gene, RNA, and targeted therapies.

Inhaled lipid nanoparticles (LNP) resulted in localized protein production in the lungs of mice and sustained protein production was enhanced through LNP repeated administration, without pulmonary or systemic toxicity.82 Inhaled LNP-based mRNA encoding cystic fibrosis transmembrane conductance regulator (CFTR) was delivered after nebulization to express the therapeutic pulmonary protein in a CFTR-deficient animal model.82 This study revealed a feasible design method for the clinical translation of mRNA therapies based on inhalable LNP.82

RNA therapies have recently made significant improvement with the approval of Nonpatrol™, an siRNA therapy delivered using a lipid nanoparticle (LNP). LNP-based mRNA vaccines against COVID-19, which were the first mRNA vaccine to be approved on market. Engineering an LNP mRNA formulation to produce a dry powder formulation made it possible to maintain stability and preserve mRNA function compared to liquid formulations.83 The enhanced green fluorescent protein (eGFP) mRNA loaded spray-dried LNPs which are delivered through the intratracheal route led to the production of eGFP protein. Protein expression detected in cell types involved in adaptive immunity and these cells could be crucial targets for inhaled vaccines against respiratory pathogens.83 Spray drying of LNPs enhanced their stability and might make RNA deliver to the lung for protein replacement therapy, gene editing, vaccination, etc.83

Inhaled Vaccines

Most vaccines are administered by injection to induce potent systemic immunity; however, they are less efficient at triggering mucosal immunity in respiratory tract diseases. Inhaled vaccines induce both mucosal and systemic immune responses, thereby providing rapid and effective protection. Inhaled vaccines can also reduce disease transmission by providing immediate protection against pathogens via the nose or mouth, thereby preventing them from entering the entire body and spreading to other people. However, only a few inhaled vaccines are currently marketed, including a live-attenuated vaccine against influenza and two viral vector vaccines that target SARS-CoV-2 (Table 5).

FluMist®, an intranasal live-attenuated vaccine, is the only nasal spray influenza vaccine approved by the US FDA in 2003. It is a vaccine sprayed into the nose to help protect against influenza in people aged 2–49 years.84 The advantage of nasally administered vaccines is the induction of local mucosal immune responses, which may block further infection and the broad transmission of respiratory pathogens. This vaccine was demonstrated to induce distinct and compartmentalized antibody responses in mucosa and blood.85 Mucosal antibodies different from blood antibodies are related to distinct immune responses early post-inoculation, offering protection against mucosal infection.85

iNCOVACC® is an intranasal vaccine based on a replication-deficient chimpanzee adenovirus backbone (ChAd36) that expresses the full-length ancestral SARS-CoV-2 S containing two amino acid substitutions in the S2 subunit.86 Its immunogenicity along with the upregulation of systemic and mucosal immune responses have been evaluated successfully in preclinical studies. Moreover, the induction of a robust systemic immune response has been shown after prime-boost immunizations in clinical trials.87 However, the vaccine stimulates only a weak upregulation of pre-existing salivary IgA, and actual data on vaccine efficacy are not available.88 Despite this, iNCOVACC® has been licensed for clinical application in India (2022).

Convidecia Air® is an orally inhaled aerosolized vaccine based on a replication-deficient human type 5 adenovirus (Ad5) vector that expresses the full-length ancestral SARS-CoV-2 spike (S) protein.89 This aerosolized vaccine is directly inhaled into the patient’s airway via a cup dispenser, similar to the natural infection way of the SARS-CoV-2. The heterologous booster regimen with aerosolized Ad5-nCoV is secure and highly immunogenic, boosting both systemic and mucosal immune responses in large-scale population.90 Aerosolized Ad5-nCoV could provide better protection against SARS-CoV-2 omicron variants than inactivated COVID-19 vaccines.90 Currently, Convidecia Air® is licensed for clinical applications in China (2022), Morocco (2022), and Indonesia (2023).

Personalized Inhalation Therapy

Inhalation therapy is a major treatment method for various respiratory diseases, and its effectiveness depends on the accuracy of medication delivery. Therefore, personalized inhalation therapy is highly desirable because inhalers should be specifically designed to suit patients’ needs (Table 5).

Examples of Cystic Fibrosis Treatment Using Personalized Inhalation Therapy

Three inhaled antibiotics (tobramycin, aztreonam, and colistimethate) have been approved for use in patients with cystic fibrosis as non-biological agents. Inhaled antibiotics are a crucial therapeutic method for cystic fibrosis, because chronic airway infection is a sign of the disease.91 The development of new formulations of antibiotics and non-antibiotic antimicrobials which may be effective for the treatment of intrinsically antibiotic-resistant organisms has opened a new era of personalized medicine.91 In a clinical trial in Denmark, it was common to change inhaled antibiotics and use off-label inhaled antibiotics in patients with cystic fibrosis.92 However, the therapeutic outcomes of personalized antibiotic inhalation prescriptions were satisfactory. Adherence to at least one daily inhalation dose was significantly higher than that to multiple daily inhalations.92

Personalized phage therapy is another promising strategy to address antimicrobial-resistant diseases, such as cystic fibrosis, which is probably worsened by recurrent pulmonary infections caused by Pseudomonas aeruginosa.93 In a specific clinical trial, patients (median age, 32 years) with cystic fibrosis were treated with phages in that they were infected with multidrug-resistant or pan-drug-resistant Pseudomonas.93 Personalized nebulized therapy using a phage trade-off strategy might influence clinical and microbiological endpoints, but this has to be evaluated in larger clinical trials.93

Discussion on the Success and Challenge of Personalized Inhalation Therapy

Personalized inhalation therapy has emerged as an effective strategy for improving treatment outcomes in chronic respiratory diseases, particularly cystic fibrosis. One major success of this approach lies in the targeted delivery of inhaled antibiotics such as tobramycin, aztreonam, and colistimethate, which achieve high local drug concentrations in the lungs while limiting systemic exposure. Clinical studies have demonstrated that individualized selection and rotation of inhaled antibiotics, including off-label use, can yield satisfactory therapeutic outcomes in patients with chronic airway infections.92 These findings highlight the clinical value of tailoring antimicrobial therapy based on patient-specific microbiological profiles and treatment responses. Another important success of personalized inhalation therapy is improved treatment adherence. Evidence from the Danish clinical trial indicates that adherence to at least one daily inhalation dose was significantly higher than adherence to multiple daily inhalations.92 This underscores the importance of considering treatment burden, inhaler design, and dosing frequency when personalizing inhalation regimens. Simplified treatment schedules aligned with patients’ daily routines may enhance long-term compliance and, consequently, clinical effectiveness.

Despite of these successes, several challenges remain. Chronic airway infection in cystic fibrosis patients is often caused by intrinsically or acquired antibiotic-resistant organisms, limiting the effectiveness of conventional inhaled antibiotics. Novel antibiotic formulations and non-antibiotic antimicrobials represent a promising extension of personalized medicine, but robust clinical evidence which can support their long-term efficacy is still limited. Additionally, heterogeneity in airway obstruction and mucus accumulation can lead to uneven aerosol deposition, reducing drug delivery to severely affected lung regions.

Personalized phage therapy also provides a novel and highly specific approach to address antimicrobial resistance, particularly in cystic fibrosis patients infected with multidrug- or pandrug-resistant Pseudomonas aeruginosa.93 Early clinical studies suggest that nebulized phage therapy may influence both clinical and microbiological outcomes. However, these findings are only based on small cohorts, larger and controlled trials are required to establish efficacy, optimize dosing strategies, and assess long-term safety.93

Although personalized inhalation therapy has demonstrated significant benefits in cystic fibrosis management, further clinical validation and technological optimization are needed to overcome current limitations and enable broader clinical implementation.

Perspectives and Challenges

The delivery of inhalation drugs is transitioning from a niche pulmonary route to a mainstream platform for systemic and precision therapies. As digital, formulation, and biological technologies converge, inhalation will play a vital role in the future of personalized treatments and patient-centric medicine. The future outlook of inhalation drugs includes expansion into non-respiratory indications (eg, central nervous system disorders, diabetes, and lung cancer), the development of next-generation inhalable excipients and stabilizers, integration with wearables and telehealth for chronic disease management, green propellants, and recyclable device components to meet sustainability goals.94–96 Although inhalation drugs are promising, they still have some challenges and limitations to overcome or evaluate (Table 6).

Table 6.

Challenges or Limitations for Inhalation Drugs

Aspect	Challenges or Limitations
Patient adaptation	Inhaled drugs may not suitable for all patients such as elderly and infants
Drug and device compatibility	Not all drugs can be effectively formulated for inhalation
	Correct use of inhalers is crucial for efficacy
Stability of formulations	Inhaled drugs must remain stable and effective in aerosol form
Pulmonary clearance mechanisms	Mucociliary clearance and alveolar macrophages can remove or degrade inhaled drugs
Tolerance	Repeated usage of inhaled drugs might induce tolerance in some patients
Quantity variability	Actual inhaled quantity may be variable (not fixed) in taking inhaled drugs every time
Inter-patient variability	Lung anatomy and inhalation effort affect inhaled drug deposition
Formulation constraints	Biologics may denature during aerosolization
Side-effect	Some patients may be allergic to inhaled drugs
Environmental impact	Hydrofluoroalkane (HFA) propellants in Metered-Dose Inhalers (MDIs) raise climate concerns
Regulatory and manufacturing considerations	Combination product approval (device + formulation) poses unique regulatory challenges
	Focus on good inhaler technique training in real-world use
	Emphasis on device-formulation compatibility in development

Conclusions

The delivery of inhalation drugs has evolved beyond the traditional treatment of asthma and COPD, and has become a promising platform for systemic therapies and precision medicine. The pulmonary route offers benefits such as rapid onset, targeted local delivery, reduced systemic side-effects, and avoidance of first-pass metabolism. Emerging trends include smart inhalers integrated with digital technology for adherence monitoring; inhaled biologics, including peptides and monoclonal antibodies; and nanoparticle-based formulations, enabling sustained release and targeted therapy. Inhaled gene and RNA therapies are under development for diseases such as cystic fibrosis and lung cancer, and inhaled vaccines are being explored to induce mucosal immunity against pathogens, such as influenza viruses and SARS-CoV-2. Advances in device engineering, including SMIs and DPIs, have enhanced patient usability and dose precision, although challenges and limitations remain (Table 6). The future of inhalation drug delivery is focused on expanding its applications beyond respiratory diseases, integrating AI for personalized treatment, developing greener technologies, and combining wearable devices for remote disease management. Overall, inhalation therapy plays an important role in the next generation of patient-centric and precise healthcare.

Disclosure

The authors report no conflicts of interest in this work.