A Preventable Alzheimer's Disease Microneedle Patch with Synaptic Protection and NLRP3 Inflammasome Suppression in Microglia during Smoking Cessation.

Long-term smoking elevates the risk of Alzheimer's disease (AD), yet it is overlooked that nicotine replacement therapy (NRT) inadvertently exacerbates tau pathology during smoking cessation. Here, we mimicked the nicotine replacement patch to design a microneedle patch for the prevention of Alzheimer's disease (PADM), capable of regulating microglia with synaptic protection and NLRP3 inflammasome suppression during smoking cessation. We first demonstrated that nicotine (NIC) transiently preserved synaptic integrity by upregulating the "do not eat me" signal SIRPα on microglia, reducing aberrant synaptic pruning and enhancing amyloid-β (Aβ) clearance in early AD. However, the NLRP3 inflammasome of microglia was activated after NIC intervention and exhibited tau hyperphosphorylation in neurons in late pathology of AD. To address this, we further integrated a natural NLRP3 inhibitor, resveratrol (RES), with NIC into a bilayer microneedle patch. The tip layer enabled sustained low-dose NIC release for smoking cessation, while the backing gel reservoir slowly released RES to suppress neuroinflammation. In APP/PS1 mice, early smoking cessation intervention improves cognition and reduces Aβ burden, and continuous RES delivery prevented late-stage tau pathology. The PADM patch offers a safe prophylactic approach to AD during smoking cessation in high-risk populations.