Since the global pandemic of SARS-CoV-2 arose, awareness of pulmonary diseases has emerged, reshaping priorities in respiratory health. Hence, pulmonary administrative delivery has garnered renewed attention for most pulmonary diseases. Inhaled therapeutics have been used for decades to treat lung diseases. It is the gold standard for the administration of low molecular-weight drugs [1]. However, the potential for expanding pulmonary delivery beyond traditional small molecules into the realm of complex biologics is now being seriously reconsidered.

Pulmonary administration has become one of the most favourable and non-invasive drug delivery techniques due to its ability to target lungs directly, reducing exposure of the used drugs to other locations [2]. Pulmonary therapeutic delivery enables administration of lower drug doses with reduced incidence of systemic adverse effects while also facilitates rapid onset of action for certain therapeutic agents [3]. Delivering therapeutics via inhalation requires navigating a highly complex biological landscape. For pulmonary delivery, the particle must cross several airway bifurcations.

While promising, there are a few setbacks in delivering therapeutics through inhalation. An example of the complexity of this system is the defence mechanism of the respiratory tract that has been established to prevent inhaled contaminants from entering the lungs and to remove or inactivate them after they have been deposited. Furthermore, an inhaling device or medium would be needed and used correctly to ensure ideal drug delivery [3]. The physical and immunological barriers in the lung are made up of mucus, the epithelial cell layer, surface fluid that is antimicrobial-rich, and neutralising immunoglobulins [4]. This barrier’s main function is to shield the airway from external hazards, but it also prevents effective drug administration. Despite these challenges, the unique physiology of the pulmonary system characterized by a vast surface area and proximity to the systemic circulation offers significant advantages for therapeutics that require rapid absorption and action, such as corticosteroids [5]. This biological “gateway” has driven increasing research interest in pulmonary delivery for more sophisticated agents, particularly biologics.

Biological therapeutics (biologics) cover a broad spectrum of products, including vaccines, blood-based substances, recombinant proteins, and somatic cells. They can be sourced from human, animal, or microbial origins and are frequently manufactured using advanced biotechnological processes. Cutting-edge treatments, such as gene-based or cell-based therapies, are at the forefront of biomedical innovation. In contrast to chemically synthesized drugs with distinct and fixed structures, many biologics are intricate blends that cannot be easily characterized. Biologics generally exhibit high specificity and lower toxicity levels compared to conventional drugs [6].

An example of a biological therapeutic is local-acting protein therapies such as Pulmozyme, a nebulized recombinant human DNAse [1] which has been commercialised for the treatment of cystic fibrosis (CF). Among protein-therapeutics, studies of antibodies-based therapeutics have also been increasing as antibodies are one of the prominent biological elements used for the targeted administration of drugs due to their framework’s stability, selectivity, and adaptability [7]. The ability of antibodies to accumulate in the target organ or tissue in a targeted, quantifiable manner regardless of the administration site and method is referred to as the use of antibodies in targeted drug delivery [8].

The goal of developing targeted pulmonary delivery systems is not merely to treat disease but to do so more safely by decreasing side effects and dosage requirements, efficiently by increasing plasma residence duration, and precisely by increasing the drug concentration at the target site, hence also improving biodistribution [9]. Nevertheless, while inhaled antibodies have shown promising preclinical and early clinical outcomes, no inhaled antibody therapies have yet been approved by major regulatory bodies such as the U.S. Food and Drug Administration (FDA) or European Medicines Agency (EMA). This gap between scientific promise and clinical approval highlights both the challenges and the untapped potential within this evolving field. Given the advancements in formulation strategies and delivery technologies, inhaled biologics are increasingly being explored as therapeutic options across a wide range of respiratory diseases. This review critically discusses recent developments in inhaled biologic therapies across various disease contexts, such as asthma, pulmonary fibrosis, chronic obstructive pulmonary disease (COPD), COVID-19 and respiratory syncytial virus (RSV). By evaluating the technologies and strategies specific to each condition, this review aims to highlight both the current progress and the future directions of inhaled biologic delivery.

Pulmonary drug delivery as preferred route for respiratory diseases

The lungs are equipped with an extensive vascular system, holding about 500 mL of blood [10]. Their structure includes a vast epithelial surface spanning over 100 m² and a thin alveolar barrier less than 1 μm thick, enabling efficient gas exchange [11]. While the lungs have robust defence mechanisms, the pulmonary route for drug delivery remains highly promising and offers great potential to address unmet medical challenges.

The pulmonary drug delivery route ensures quick symptom relief due to the rapid onset of action, which is especially important during acute exacerbations [11]. In clinical settings, the rapid therapeutic onset provided by inhalation could be critically advantageous, especially in managing acute respiratory distress events where systemic drug administration might be too slow. Inhalation therapy requires a smaller dose compared to systemic administration, and it minimizes systemic exposure, significantly lowering the likelihood of side effects affecting the entire body [12].

A review comprising the administration of monoclonal antibodies via systemic administrations on COVID-19 has reported that the concentration of monoclonal antibodies (mAbs) in the lungs is typically reduced by 500–2000 folds than in the bloodstream [13,14,15]. Hence, inhalation delivery offers a more effective approach as it allows a significantly higher proportion of the administered mAbs to reach the target area directly within the airways [16]. This striking inefficiency of systemic administration strongly supports the argument for shifting towards direct inhalation methods to maximize therapeutic availability at the infection site. This approach ensures elevated and longer-lasting drug levels at the disease site, eliminating the need for large doses administered systemically.

Administering drugs directly to the lungs through inhalation can achieve both local and systemic therapeutic effects. Importantly, this dual-action capability underscores the versatility of pulmonary delivery, suggesting it could bridge the gap between targeted and systemic therapies, depending on the disease. Compared to other administration routes, pulmonary inhalation offers significant advantages such as a large absorption area with a thin alveolar epithelial cell membrane that facilitates rapid absorption and high permeability. This ensures rapid concentration of medication at the target site while keeping systemic drug levels low [17].

Considering how pulmonary route is particularly advantageous, when compared to oral delivery, albeit the convenience and non-invasive technique, it is often related to its poor bioavailability due to enzymatic degradation and first-pass metabolism in the liver, making it unsuitable for many biologics specifically the proteins and peptides [18]. In contrast to inhaled delivery route as it bypass hepatic first-pass metabolism primarily due to their route of administration, as they are directly delivered to the respiratory tract rather than absorbed via the gastrointestinal system. This results in reduced systemic metabolism and allows for higher local drug concentrations at the site of action, potentially improving therapeutic efficacy and also reduces systemic exposure [19].

If compared to intravenous and subcutaneous administrations, both are invasive in nature but has differences in their pharmacokinetic profiles. Intravenous delivery provides 100% bioavailability and rapid systemic distribution, but it requires clinical supervision and often fails to achieve sufficient drug concentration in the lungs, particularly for monoclonal antibodies targeting respiratory infections [20]. In contrast, subcutaneous injections, though more convenient than IV, are associated with delayed absorption and similarly result in limited pulmonary drug levels [21]. Hence, from a patient-centric perspective, the non-invasive nature of inhalation paired with the potential for dose reduction and fewer systemic side effects may enhance therapeutic adherence compared to injectable regimens [22]. These advantages make pulmonary delivery an attractive alternative for administering biologics.

The first traction of pulmonary drug delivery was in the 1950s specifically for asthma treatment and has become a widely accepted approach for managing respiratory conditions since. While initially developed for asthma management, the maturation of inhalation technologies now offers much broader therapeutic possibilities, extending well beyond classical respiratory conditions. Utilizing devices to spray or nebulize drug aerosols, this technique enables patients to breathe in medication, allowing faster achievement of peak lung concentration (Cmax) [23]. Animal studies have highlighted the superior efficiency of the inhalation drug delivery route as compared to intravenous or intraperitoneal administration for delivering mAbs targeting respiratory viruses like influenza and RSV. Furthermore, researchers observed that 1.7% of inhaled mAb 1212C2, a strong neutralizing antibody against SARS-CoV-2, reached the bronchoalveolar lavage fluid (BALF) of hamsters within 30 min of inhalation. In contrast, the intraperitoneal route resulted in less than 0.1% lung deposition of the same antibody [24]. These findings offer compelling preclinical validation that pulmonary delivery not only improves drug targeting efficiency but may also enable substantial dose reductions, minimizing costs and potential systemic side effects.

Device considerations for inhaled biologics: bridging formulation and function

Effective pulmonary drug delivery depends not only on therapeutic agent, but also on the delivery method used. Various inhalation devices have been developed to optimize drug deposition in the lungs, particularly for patients with respiratory diseases such as asthma and COPD. Understanding the physiological requirements and device-speicific characteristics is crucial for achieving targeted delivery and therapeutic success. The following section outlines key considerations and the strengths and limitations of each delivery platform as shown in Table 1.

The physicochemical characteristics of aerosols, such as their shape, size, density, and hygroscopicity, play a crucial role in determining how inhaled particles are deposited within the lungs [25]. Among these factors, the aerodynamic diameter of particles is particularly significant for dictating their distribution across various regions of the respiratory system. In order to establish an effective pulmonary delivery, inhaled biologics must be able reach and remain in the intended region of the lung. This is largely determined by the aerodynamic diameter of the particles. Particles with diameters ranging from 1 to 5 μm have been found to deposit more effectively in the lungs, which in turn enhances their potential therapeutic efficacy [26, 27]. Particles smaller than 1 μm may be exhaled before deposition, while those larger than 5 μm tend to deposit in the oropharyngeal region, thereby failing to reach deeper lung tissues [28, 29]. This structure of size depositions of inhaled particles in the respiratory system is shown in Fig. 1 [30].

Fig. 1

Illustration of size depositions of inhaled particles in the respiratory system. (a) Structure of the upper airway of the human lung. Mouth inlet is idealized, while the trachea and bronchi are obtained from a healthy adult male [31]. Generations 0–3 (G0–G3) are labeled, and representative generations are indicated for the lobar and segmental bronchi. (b) Diagram depicting the role of aerodynamic diameter (dae) in generational deposition within the lung, where ∼10-µm aerosols deposit in the oropharynx and trachea, ∼5-µm aerosols deposit in the upper conducting airways, and ∼1-µm aerosols reach the respiratory airways [28]. Illustration adapted from [32]

Once deposited, the pharmacokinetics of the therapeutic agent are influenced by its molecular size and biochemical properties. Inhaled agents must also overcome shifts in humidity, penetrate the airway lining, and bypass various cellular defence mechanisms. The pulmonary immune landscape includes resident immune cells that play essential roles in maintaining airspace integrity, clearing inhaled particles, and initiating localized immune responses. Among these, alveolar macrophages, CD11b + and CD103 + dendritic cells, and interstitial macrophages are of particular interest, as they are involved in numerous respiratory pathologies [33].

In addition to deposition, effective pulmonary delivery requires adequate residence time within the lungs [34]. The retention and clearance of inhaled biologics can vary significantly depends on their size and structure. Monoclonal antibodies, due to their large molecular weight (~ 150 kDa), often show prolonged retention in the lung interstitium but are more prone to enzymatic degradation or uptake by alveolar macrophages [35,36,37]. In contrast, nanobodies and peptides, owing to their smaller sizes exhibit improved tissue penetration but shorter half-lives [38], necessitating formulation strategies like PEGylation [37, 38] or encapsulation [38] to enhance stability and residence time.

Methods of pulmonary delivery include pressurized metered-dose inhalers (pMDIs), dry powders for inhalation (DPIs), and nebulizers [25] as shown in Fig. 2. Deciding between various options involves careful consideration of multiple aspects, such as the physicochemical characteristics of the drug, the simplicity of its application, the patient’s age, and the feasibility of manufacturing on an industrial scale [26]. Inhaler and the formulation design must also account for lung physiology, including mucociliary clearance, surface liquid thickness and alveolar macrophage activity, all of which influence particle retention and absorption [21]. Therapeutic aerosols must meet specific criteria regarding their aerodynamic particle size to be effective.

pMDIs include a pressurized canister containing a drug-propellant mixture that delivers medication in a fine mist upon actuation. It is often used with spacers to improve drug deposition. The advantages of using pMDIs are the portability, hand-held design, and the ability to deliver accurate doses with each actuation. However, reports have shown that excessive drug deposition was found in the oropharyngeal region, necessitating higher dosage levels to achieve therapeutic effects at the target site when using this device [26, 39]. DPIs have been manufactured to aid patients mainly suffering from asthma and COPD. Several manufacturers of DPIs produce active systems equipped with an external energy source to aid in the deagglomeration of the powder. These devices are particularly beneficial for individuals with reduced breathing capacity, such as children, critically ill patients, and those suffering from severe COPD or asthma [40]. The first researchers to introduce the use of DPI technology were Bell et al., where they demonstrated the ability of the device to dispense size-graded fractions of lactose, in the range of 4–400µ [41].

The emerging technology of the development of pressurized breath-activated inhalers (BAIs) aim to integrate the advantages of pMDIs and DPIs while addressing their shortcomings. For instance, devices such as Synchrobreathe™ operate by detecting low efforts of inhalation and synchronizing dose delivery with the breathing process, thereby eliminating the challenge of coordinating the two actions [42]. BAIs offer various benefits, including user-friendliness, efficient therapeutic delivery to the lungs, and greater patient preference. The future of medicine is set to prioritize tailored biological therapies and advancements in drug delivery systems. Smart inhalers integrated with sensors are also emerging, which track inhalation parameters and adherence, offering personalized dosing and real-time feedback for improved clinical outcomes [43, 44].

Nebulizers consist of three different categories which are jet nebulizers, ultrasonic nebulizers, and mesh nebulizers where the technology depends on the properties of drug solution into aerosols [26, 45]. The introduction of early nebulizers dates back to the mid-19th century, marking the initial step in aerosol medicine delivery. Later, between the 1930s and 1950s, advancements led to the creation of both electric nebulizers and hand-bulb models, further revolutionizing respiratory therapy [46]. Nebulizers operate effectively with tidal breathing and do not demand extensive patient training or cooperation. They are generally used for diseases that require high pulmonary doses and patients who are unable to achieve the necessary flow rate. As a result, they are particularly beneficial not only in emergencies but also for elderly and paediatric patients who may have cognitive or physical challenges [26, 45].

pMDIS are typically not suitable for delivering biologics due to the propellant-protein compatibility issues [30]. When administering drugs, the formulation would only content approximately 1% of the active drug with typically delivering less than 0.5 mg of medication per actuation [47, 48]. Studies have reported that only 10–20% of the drug dosage deposited by pMDIs is concentrated in the lungs [49]. DPIs on the other hand have better stability to deliver biologics with the ability to effectively aerosolize large masses (25–100 mg) of spray dried powder formulations [50, 51]. In comparison with nebulizers, they are capable of administering significantly large doses, often exceeding 100 mg, making them more suitable for therapies requiring higher drug loads [48]. Hence, more new developments of aerosol medications and most biologics involved requires nebulizer delivery.

The selection of an inhaler is also influenced by various patient-specific factors. This includes the patient’s inspiratory flow rate and volume, severity of the condition, presence of other health issues, and the patient’s ability to use the device [52]. It is also influenced by the properties of the developed formulation in consideration of the particle size and aerosol velocity generated by the device as well as the regimen complexity of inhalation therapy [53].

Table 1 Shows a comparison of pulmonary drug delivery devicesFig. 2

Types of inhalable devices for pulmonary delivery

Inhaled biologics across respiratory pathologies: current strategies and emerging evidence

When delivering biologics specifically proteins, a main concern is protein degradation during administration. When proteins lack stability in their solution form, they can be enhanced with stabilizing agents before undergoing freeze-drying or spray-drying processes for preservation [54, 55]. These approaches allow the proteins to be reconstituted effectively, making them suitable for delivery through nebulizers. Studies have shown that aerosols produced using mesh nebulizers specifically the vibrating mesh technology significantly minimize protein degradation compared to jet or ultrasonic nebulizers, which rely on heating elements [14, 56]. While traditional jet nebulizers deliver medication with an efficiency of approximately 10%, newer vibrating mesh nebulizers (VMNs) surpass 60% efficiency, tackling challenges often seen in dry powder formulations for proteins such as hygroscopic growth and protein aggregation. Additionally, these devices eliminate the need for synchronized breathing techniques that are frequently required with dry powder inhalers or metered dose inhalers, which can pose difficulties for both elderly and paediatric users [14, 15].

Limitation of MDI that may occur to delivering biologics are such as the hydrophilic nature of most biologics and poorly soluble in the non-polar hydrofluoroalkane (HFA) propellants used in MDIs. This poor solubility limits the formulation possibilities and the dose range that can be delivered per actuation [57]. Besides that, MDIs often result in high oropharyngeal deposition and require precise coordination between actuation and inhalation. This can lead to suboptimal lung deposition, especially in patients who have difficulty with inhaler techniques [58]. Hence, nebulizers are highly favoured for administering proteins due to the simplicity of their formulations and the compatibility with soluble proteins, which require minimal use of additives.

Given the continuous advancements in formulation techniques and delivery technologies, inhaled biologics are emerging as promising therapeutic options for a wide range of respiratory disorders. This section provides a comprehensive analysis of recent developments in inhaled biologic therapies, focusing on diseases such as asthma, pulmonary fibrosis, COPD, COVID-19, and respiratory syncytial virus (RSV). By evaluating the specific delivery strategies and technologies for each condition, this review aims to highlight both current progress and future directions in the field. A summary of the key findings discussed is presented in Table 2.

Table 2 Shows a summary of the key findings discussed in section belowInhaled biologics for asthma: direct targeting of TSLP and IL-13 pathways

Asthma is a common and persistent respiratory illness that impacts millions worldwide. Its symptoms include wheezing, breathing difficulties, chest tightness, and coughing. The condition has a far-reaching effect, with approximately 262 million people affected in 2019, predominantly children, resulting in significant mortality and economic burdens. Recent data from the Global Initiative for Asthma (GINA) 2024 Report indicates the global asthma population has now approached 300 million individuals [76].

The pharmacological management of asthma is divided into several categories such as rescue therapies, controller treatments, and, for severe cases, add-on options. Reliever medications play a key role in addressing acute symptoms, while controller therapies are designed to minimize airway inflammation. For patients with severe asthma, particularly those with an eosinophilic phenotype, biologic treatments are often recommended. These patients typically continue to experience symptoms and frequent exacerbations despite using high-dose inhaled corticosteroids (ICS) combined with long-acting beta-agonists (LABA). Current biologic therapies target molecules such as immunoglobulin E (IgE), IL-4, IL-5, IL-13, and thymic stromal lymphopoietin [77]. The EMA and the U.S. FDA have approved six biological treatments, including omalizumab (anti-IgE), benralizumab, mepolizumab, reslizumab (anti-IL5/IL5R), dupilumab (anti-IL-4Rα/IL-13), and tezepelumab (anti-TSLP) [78,79,80,81,82]. While systemic biologics have made significant strides, it is notable that inhaled options could offer a transformative step forward by delivering treatment directly to the site of inflammation with reduced systemic exposure. However, all approved biological therapies are administered via systemic routes, including intravenous and subcutaneous methods.

Systemic administration of biologics is associated with key limitations such as low pulmonary bioavailability due to distribution dynamics, reducing local efficacy [83]. Moreover, systemic exposure increases the risk of adverse effects including hypersensitivity reactions, generalized immunosuppression and potential toxicity. Biologics delivered systemically may also exhibit delayed onset due to longer absorption and distribution phases [84]. These limitations underscore the need for direct, localized delivery methods that can improve drug concentrations in lung tissue while minimizing systemic exposure. Such approaches may also enhance patient adherence by reducing the invasiveness and complexity of treatment regimens.

Thymic stromal lymphopoietin (TSLP), a cytokine produced by epithelial cells, plays a critical upstream role in the development of asthma. TSLP is involved in activating dendritic cells, which leads to the differentiation of naïve T cells into Th2 cells. These Th2 cells then produce cytokines such as IL-4, IL-5, and IL-13 (Fig. 3) [16]. Research suggests that inhibiting TSLP with the monoclonal antibody Tezepelumab which is currently the only approved add-on treatment could benefit a wide range of asthma patients [85], however, limited to systemic administration methods, necessitating regular injections. Reliance on systemic administration may hinder the full therapeutic potential of TSLP-targeting agents due to the difference in dosing schedules and limited drug targeting, inhaled biologic therapies targeting TSLP could offer a practical alternative by improving local pharmacodynamics and reducing systemic side effects.

A recent study reported by Gauvreau et al., has developed ecleralimab as the pioneering inhaled anti-TSLP therapy aimed at treating asthma [