High frequency capillary wave-enabled ultra-small droplets for inhaled drug delivery

Benefiting from localization, targeting and rapid response, inhaled drug delivery has become an indispensable method for treating lung diseases. However, the efficacy of drug delivery is often compromised by the physical characteristics of the aerosol produced by current nebulization methods, <i>i.e.</i>, large droplet size distributions, which are deposited in the upper airways. In this study, a portable, low-energy, and low-cost approach to nebulize drugs with appropriate size distribution is introduced using capillary wave breakup induced by gigahertz (GHz) acoustic waves. A delicately designed miniaturized nebulizer is developed by integrating a GHz bulk acoustic resonator with a semi-open microchannel to nebulize droplets of optimal size for pulmonary inhalation, with size distributions, in which 96% are smaller than 5 μm at low power, which surpasses existing methods. In addition, this technique facilitates the nebulization of liquids with viscosities of up to 5000 cP. Low-flux lung models achieve 88% drug delivery efficiency. Murine <i>in vivo</i> tests demonstrate the efficacy of the proposed nebulizer in lung-targeted delivery <i>via</i> autonomous inhalation, which is attributed to optimized droplet size and flux. The tunable sizes, broad range of nebulization viscosities, suitable fluxes, pumpless operation, and low cost highlight the potential for autonomous lung drug delivery and combination therapy targeting both the small airways and alveoli.