Dual engine-driven bionic microneedles for early intervention and prolonged treatment of Alzheimer's disease.

The microneedle (MN) delivery system presents an attractive administration route for patients with Alzheimer's disease (AD). However, the passive drug delivery mode and low drug loading of MNs often result in unsatisfactory therapeutic efficiency. To address these dilemmas, we developed dual engine-drive bionic MNs for robust AD treatment. Specifically, free rivastigmine (RVT) and RVT particles were co-loaded within the MNs to construct the valve and chambers of the guava, respectively, which can serve as an active engine to promote drug permeation by generating capillary force. K2CO3 and citric acid were introduced as a pneumatic engine into the MNs to promote the permeation of free RVT into deeper skin layers for early intervention in AD. Further, the RVT particles served as a drug depot to provide continuous drug release for prolonged AD treatment. Compared with free RVT-loaded MNs, the dual engine-driven bionic MNs showed an increase in drug loading, cumulative transdermal permeability, and normalized bioavailability of approximately 40%, 22%, and 49%, respectively. Pharmacodynamic studies further confirmed that the dual engine-driven bionic MNs were most effective in restoring memory and recognition functions in mice with short-term memory dysfunction. Therefore, the dual engine-driven bionic MNs hold great promise for highly efficient AD treatment.