Microglia, as the immune cells of the central nervous system (CNS), play dynamic roles in maintaining neuronal health and contributing to various neurological conditions. However, it is challenging to explore the molecular mechanisms that drive microglia function because traditional viral approaches such as Adeno-Associated Virus (rAAV) are not compatible with microglia. Conventional AAV-based microglia targeting, whether through microgliaspecific promoters or AAV capsid engineered expressing transgene in vitro and in vivo, often results in low transduction efficiency and unstable transgene expression. This limitation arises from a lack of understanding of the underlying mechanisms that reduce AAV microglia transduction, which, if addressed, could improve transduction efficiency. To circumvent this limitation, we develop a AAV based microglial compatible gene therapy approach. We first screen rAAV capsids that can target the microglial receptor protein (MRP). We will identify efficient rAAV variants from an AAV library using naturally expressed or genetically modified microglial engineered to express MRP in vitro and in vivo. To this end, we will initially screen for the most effective MRP, either P2Y12 or TMEM119, in mouse microglial cell lines BV2 and SIM-A9. This will be achieved through immunohistochemistry, size analysis, and protein homology matching with human protein sequences to facilitate future clinical applications. Finally, the most efficient MRP will be overexpressed in HEK cells to pull down rAAV variants from the AAV library, which will then be further characterized using deep DNA sequencing. The top-performing capsid variants will be used for AAV packaging to express transgenes or GFP in vivo in the mouse brain. This design strategy enhances the precision and efficacy of gene therapy applications to microglia, facilitating AAV-mediated microglial targeting for therapeutic interventions in neurological disorders.