Restoring lysosomal homeostasis in microglia via a catch-and-patch nanomedicine for Alzheimer’s disease

Lysosomal homeostasis acts as the tipping point at Aβ deposition and clearance, critically dictating the trajectory of Alzheimer’s disease (AD) pathology. While monoclonal antibodies have shown promise in reducing extracellular Aβ burden, they inadvertently induce a massive Aβ influx into microglia that overwhelms the lysosomal degradation capacity. The Aβ overload results in toxic intracellular Aβ spillover and increases the risk of inflammatory side effects. We show that the AMPK-TFEB axis is essential for maintaining microglial function by regulating lysosome activity and Aβ clearance. Building on this insight, we develop a polymeric micelle capable of removing both extracellular and intracellular Aβ while preserving intracerebral homeostasis. This nanomedicine facilitates microglial endocytosis of Aβ deposits and stimulates TFEB-mediated lysosome biogenesis in a pH-responsive manner, thereby expanding the lysosomal capacity to manage the Aβ influx. Through this “catch-and-patch” mechanism, it functions as an Aβ scavenger and stabilizes microglial activity at a steady-state setpoint. Intravenous administration of the micelle significantly reduces Aβ burden and mitigates cognitive decline in 5xFAD mice. Minimal cerebral amyloid angiopathy or inflammation is observed compared to anti-Aβ antibody therapy. We provide a proof of principle for safe and effective AD treatment by synergistically targeting the extracellular-intracellular Aβ cascade.