Rocket-inspired gas-propelled microneedles engineered with borneol-NLCs-loaded hierarchical cavities for enhanced brain delivery in Alzheimer's therapy.

Microneedle technology has emerged as a promising transdermal platform for transdermal delivery of Alzheimer's disease therapeutics. However, conventional passive diffusion approaches face fundamental limitations in overcoming both skin and blood-brain barriers. To address these limitations, we developed a rocket-inspired gas-propelled microneedle system integrating nanostructured lipid carriers for enhanced dual-barrier penetration. The study combined fluid vortex generation with blood-brain barrier endothelial remodeling to achieve efficient drug delivery. Specifically, the system featured a hierarchical cavity design with borneol-modified huperzine A-loaded nanostructured lipid carriers (NLCs) (particle size: 89.6 ± 0.7 nm; zeta potential: -22.5 ± 0.5 mV; Hup A encapsulation efficiency: 83.40 ± 1.51%; drug loading capacity: 2.63 ± 0.06%) in primary cavities and a spatially isolated pneumatic initiator (ascorbic acid/sodium bicarbonate) in secondary cavities. Through multiphysics simulation coupled fluid dynamics with chemical reaction kinetics and mass transport phenomena, which revealed that acid-base reactions generate CO2 microbubbles capable of producing rapid thrust forces. This microbubble-mediated propulsion mechanism achieved a 50% increase in penetration depth (up to ∼ 1428 µm) relative to conventional microneedle platforms. Remarkably, this innovative hierarchical cavity design achieved a high drug loading capacity of 182 μg/array while preserving spatial isolation between the reactants and therapeutic payload. In vivo studies validated efficient brain delivery, as evidenced by a marked increase (p < 0.001) in cortical acetylcholine concentrations and amelioration of scopolamine-induced spatial memory impairments in rat models. This work established a preclinical proof-of-concept for the enhanced brain delivery of therapeutics in neurodegenerative disease through the synergistic integration of gas-propulsion physics and advanced nanocarrier engineering, offering new possibilities for overcoming biological delivery barriers.