Brain-targeting nanocages treat Alzheimer's disease via regulating microglial polarization and remodeling microenvironment.

Alzheimer's disease (AD) is a common neurodegenerative disease that mainly occurs in the elderly population. Aberrant activation of M1-type microglia is a hallmark of AD-associated neuroinflammation. Therefore, fabricating smart brain drug delivery systems that can target and regulate the phenotype of microglia represents a promising strategy to treat AD. Herein, an engineered apoferritin (AFn) nanocage was fabricated to encapsulate salmeterol (Sal), and its surface was further modified with arginine-6 (R6). AFn-Sal-R6 (termed ASR) could cross the blood-brain barrier (BBB) via transferrin receptor 1 (TfR1) mediated transcytosis and further be internalized by microglia in the presence of R6. In an acidic inflammatory microenvironment, the cage-like structure of AFn gradually expands and ultimately releases salmeterol. The in vitro and in vivo experimental results collectively confirmed that ASR could effectively promote the repolarization of pro-inflammatory M1 microglia, thereby improving the learning and cognitive abilities of AD mice. Overall, this study provided a promising approach to mitigate AD via regulating M1/M2 microglia polarization.