Inhaled Biologics: Overcoming Challenges and Recent Advances

Biologics represent a major advance in therapy, offering highly specific and potent treatment options for diseases previously difficult to manage; however, their administration routes are commonly limited to injection due to poor oral bioavailability, which can lead to patient inconvenience and adherence challenges. The pulmonary route offers a promising alternative, leveraging the lung's large absorptive surface area, thin alveolar-capillary barrier, rich vascularization, and avoidance of first-pass metabolism to enable both local and systemic delivery. Effective inhaled biologic therapies require harmonizing the drug's physicochemical properties with aerosol aerodynamic behavior and dissolution. The pharmacokinetic fate of inhaled biologics is further influenced by lung physiology, including airflow dynamics, airway structure, mucociliary clearance, and respiratory lining fluid composition. These factors present significant barriers to the stability, absorption, and retention of inhaled biologics. Extensive research efforts focus on optimizing formulations, inhalation devices, and excipients, alongside deepening the understanding of the biopharmaceutical characteristics of inhaled biologics. This review summarizes recent advances in inhalation systems of therapeutic peptides and proteins for systemic and local effects, emphasizing practical strategies to overcome key biopharmaceutical and physicochemical challenges, thus advancing the clinical potential of next-generation inhaled biologics.