Developing a new drug from scratch costs billions of dollars and takes over a decade. Yet some of the most exciting advances in medicine do not come from discovering new molecules — they come from rediscovering old ones. Drug repurposing, the practice of finding new uses for existing compounds, has accelerated discoveries across oncology, infectious disease, and neurology (Pushpakom et al., 2019). But one repurposing strategy remains underexplored: changing not what a drug does, but how and where it is delivered. When a medicine designed for one route meets a different entry point into the body, the therapeutic story can change dramatically.
The Logic Behind Repurposing
Drug repurposing has classically meant taking an approved compound and applying it to a new disease indication. Sildenafil, developed for cardiovascular hypertension, became the cornerstone of erectile dysfunction treatment. Thalidomide, once notorious for teratogenic effects, re-emerged as a therapy for multiple myeloma (Ashburn & Thor, 2004). The appeal is straightforward: safety and pharmacological profiles are already partially understood, which shortens development timelines and reduces regulatory hurdles (Corsello et al., 2017).
Route repurposing follows the same logic with a different lever. Rather than targeting a new disease, the same drug is redirected through a different delivery pathway — changing where it acts, how the body processes it, and what kind of immune or therapeutic response it produces.
Why the Route of Administration Matters
The route through which a medicine enters the body is not a logistical detail — it determines biodistribution, metabolism, interaction with local tissues, and the nature of immune responses elicited. Oral administration exposes drugs to the gastrointestinal environment and first-pass hepatic metabolism, which can substantially reduce bioavailability (Liang et al., 2020). Pulmonary delivery, by contrast, targets the lung directly — an organ with a surface area exceeding 100 m², extensive vascularisation, and relatively low enzymatic activity (He et al., 2022).
For therapies aimed at respiratory diseases, this distinction is critical. As discussed in the previous ScientistsHub article Beyond the Needle: The Rise of Inhalable Vaccines, pulmonary delivery can stimulate both local mucosal immunity and systemic responses simultaneously — a combination difficult to achieve through oral or injectable routes (Lavelle & Ward, 2022). The site of antigen encounter shapes the character of the immune memory generated
Bacterial Lysates: A Textbook Case
Bacterial lysates (BL) are immunomodulatory agents derived from inactivated bacteria. For decades, formulations such as OM-85 (Broncho-Vaxom) have been administered orally to reduce the frequency of recurrent respiratory infections, particularly in children and individuals with chronic obstructive pulmonary disease (De Benedetto & Sevieri, 2013). The mechanism relies on gut-associated lymphoid tissue: antigens absorbed through intestinal M cells stimulate dendritic cells, promoting immune responses that eventually reach the respiratory tract (Kearney et al., 2015).
Yet clinical evidence for oral BL remains inconsistent. The European Medicines Agency reviewed available data and concluded that these medicines should only be indicated for the prevention of recurrent respiratory infections — not the treatment of existing infections nor pneumonia prevention — citing insufficient and heterogeneous evidence (EMA, 2019). Variable efficacy across trials continues to fuel scientific debate (Esposito et al., 2018).
This is precisely where route repurposing enters the picture. If the respiratory mucosa is the target of pathogen attack, delivering antigens directly there — rather than relying on the gut-lung immune axis — is a compelling scientific proposition.
Evidence for the Inhaled Approach
Recent research has tested this hypothesis by encapsulating BL within locust bean gum (LBG) microparticles engineered for pulmonary delivery via spray drying (Pinto da Silva et al., 2025). The resulting particles, with aerodynamic diameters of approximately 4.6 µm, were designed to deposit preferentially in mid-lung regions where antigen-presenting cells concentrate. As explored in APCs as Allies: How Drug Delivery Hijacks Immunity, efficient phagocytosis by macrophages and dendritic cells is essential for triggering downstream adaptive immune responses.
In animal studies, inhaled BL-loaded microparticles induced statistically significant mucosal IgA responses in bronchoalveolar lavage fluid — an outcome not observed with oral BL administration — while using only one-quarter of the antigen dose (Pinto da Silva et al., 2025). Systemic IgG2a responses, indicative of Th1-biased immune activation, were similarly significant for both routes when pooled samples were analysed. The LBG polymer has a galactomannan structure recognised by mannose receptors on macrophages — a targeting mechanism detailed in More than Lactose: Natural Polymers Revolutionizing Inhaled Drug Delivery (Rodrigues & Grenha, 2015).
The formulations also exhibited strong mucoadhesive properties, potentially extending residence time in the lung and prolonging antigen-APC contact — a feature that distinguishes particulate pulmonary delivery from simple nebulised solutions (Pinto da Silva et al., 2025).
What This Means for Medicine's Future
Route repurposing offers a pragmatic development pathway. Changing how an approved compound is delivered rather than reinventing the molecule avoids the full cost of de novo drug discovery while addressing clinical gaps that the original formulation could not fill. For BL, the inhaled route may resolve what oral therapy has struggled to achieve: generating immunity precisely at the site of pathogen entry, with lower antigen doses and fewer systemic exposures.
The dry powder format carries additional advantages that extend beyond immunology. As outlined in The Stability Problem: Why Your Medicine Needs a Cold Chain, liquid vaccine formulations demand refrigeration that limits access in low-resource settings. Dry powder inhalers eliminate cold-chain dependency, a practical benefit with significant implications for global respiratory health (de Boer et al., 2017). From Liquid To Powder: The Spray Drying Revolution In Medicine covers how this manufacturing approach makes such formulations feasible at scale.
Conclusion
Repurposing is not only about old molecules finding new disease indications. Changing the route of administration can fundamentally alter a drug's interaction with the immune system, its local efficacy, and its clinical relevance. The work being done on inhaled bacterial lysates illustrates this with clarity: a therapy with decades of oral use may reach its full potential when delivered directly to the lungs. As drug development costs rise and antimicrobial resistance intensifies, route repurposing offers a rigorous, evidence-driven path forward — and one the field is only beginning to explore.
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