Mechanistic design, translational challenges, and future perspectives of multi-drug nanoparticle-based dry powder inhalers for pulmonary therapy.

Pulmonary diseases such as chronic obstructive pulmonary disease, lung cancer, cystic fibrosis, and drug-resistant respiratory infections often involve multiple pathological pathways that may require coordinated pharmacological intervention. Although multidrug therapy can improve therapeutic efficacy and overcome resistance, conventional combination regimens frequently fail to maintain appropriate drug ratios and synchronized exposure at the pulmonary target site. Nanoparticle-based dry powder inhalers (nano-DPIs) offer an opportunity to address these limitations by integrating multidrug loading, controlled release, and inhalation-based pulmonary delivery within a single platform. However, the available evidence indicates that co-loading multiple drugs does not inherently translate into therapeutic synergy. This review critically examines the relationship between nanocarrier architecture, powder engineering, aerosol performance, pulmonary deposition, and drug exposure in multidrug nano-DPIs. Rather than treating co-encapsulation as an intrinsically superior strategy, we evaluate how drug physicochemical compatibility, loading capacity, drug-ratio preservation, release kinetics, particle engineering, and aerosolization collectively influence therapeutic coordination. Particular emphasis is placed on the critical trade-offs between nanoparticle-level performance and powder-level aerosol behavior, as well as between formulation complexity and translational feasibility The available evidence suggests that preservation of the formulation drug ratio does not necessarily ensure preservation of the therapeutically relevant ratio after aerosolization, lung deposition, dissolution, and cellular uptake. Accordingly, the rational design of multidrug nano-DPIs should shift from maximizing co-encapsulation toward achieving coordinated drug exposure at the site and time of action. Polymeric, lipid-based, and hybrid nanocarriers are therefore critically compared according to their effects on drug loading, encapsulation efficiency, stability, release behavior, aerosolization, and scalability. Emerging nano-in-micro approaches are further evaluated as a means of reconciling nanoscale therapeutic functionality with the aerodynamic requirements of pulmonary delivery. Finally, the review identifies major translational barriers related to reproducibility, powder stability, device dependence, pulmonary safety, scale-up, Qbd implementation, and regulatory characterization. By integrating formulation science, aerosol engineering, pharmacological interaction, and translational considerations, this review proposes a mechanism-based framework for designing multidrug nano-DPIs in which therapeutic coordination, rather than co-encapsulation alone, represents the central design objective.