Science

Yanxia Rao, Yunshang Bai, Xiaoyu Li, Bingying Du, and Bo Peng

Microglia are indispensable for the central nervous system (CNS) development and homeostasis, and mutations in microglia can cause microgliopathies. Correcting these mutations holds therapeutic potential, but
conventional gene therapies cannot yet achieve the CNS-wide delivery required for meaningful treatment. Microglia replacement has emerged as a groundbreaking paradigm that removes pathogenic microglia and introduces healthy donor cells. Over the past 5 years (2020–2025), the field has advanced rapidly from first
achieving efficient replacement in animals to first-in-human clinical interventions. Here, we summarize microgliopathies as therapeutic targets and trace the historical and technical evolution from the pre-replacement
era of low-engraftment approaches to efficient strategies enabling widespread replacement. We outline the
mechanistic principles and current methods that underpin efficient replacement. We highlight therapeutic
applications ranging from gene correction to engineered ‘‘Trojan horse’’ microglia and explore potential ability enhancement. Finally, we dis