Tau fibrils induce nanoscale membrane damage and nucleate cytosolic tau at lysosomes. Tau aggregates, associated with Alzheimer's disease, are thought to enter cells via endocytosis and escape into the cytosol through an unknown mechanism. This study shows that in primary astrocytes and neurons, endocytosis of tau seeds leads to their accumulation in lysosomes, causing lysosomal swelling, deacidification, and recruitment of ESCRT proteins, but not Galectin-3. These findings suggest that tau seeds escape from lysosomes via nanoscale membrane damage rather than wholesale rupture, and that cytosolic tau aggregation begins as soon as tau fibril ends emerge from the lysosomal membrane. The study used live cell imaging and STORM superresolution microscopy to show that cytosolic tau nucleation occurs primarily at the lysosome membrane. The data indicate that lysosomal membrane damage, sensed by ESCRT proteins, triggers the templated aggregation of cytosolic tau at the lysosome surface. The study also found that tau fibrils deacidify lysosomes, leading to increased lysosomal pH and recruitment of ESCRT proteins. The findings suggest that tau fibrils are robust inducers of nanoscale lysosomal membrane damage and ESCRT recruitment, which may be important for the spread of other amyloid aggregates in the brain. The study highlights the importance of understanding the ESCRT-dependent damage response and potentially targeting it for therapeutic strategies to prevent the spread of neurodegenerative diseases.Tau fibrils induce nanoscale membrane damage and nucleate cytosolic tau at lysosomes. Tau aggregates, associated with Alzheimer's disease, are thought to enter cells via endocytosis and escape into the cytosol through an unknown mechanism. This study shows that in primary astrocytes and neurons, endocytosis of tau seeds leads to their accumulation in lysosomes, causing lysosomal swelling, deacidification, and recruitment of ESCRT proteins, but not Galectin-3. These findings suggest that tau seeds escape from lysosomes via nanoscale membrane damage rather than wholesale rupture, and that cytosolic tau aggregation begins as soon as tau fibril ends emerge from the lysosomal membrane. The study used live cell imaging and STORM superresolution microscopy to show that cytosolic tau nucleation occurs primarily at the lysosome membrane. The data indicate that lysosomal membrane damage, sensed by ESCRT proteins, triggers the templated aggregation of cytosolic tau at the lysosome surface. The study also found that tau fibrils deacidify lysosomes, leading to increased lysosomal pH and recruitment of ESCRT proteins. The findings suggest that tau fibrils are robust inducers of nanoscale lysosomal membrane damage and ESCRT recruitment, which may be important for the spread of other amyloid aggregates in the brain. The study highlights the importance of understanding the ESCRT-dependent damage response and potentially targeting it for therapeutic strategies to prevent the spread of neurodegenerative diseases.