Autophagosome-targeting single-domain antibody clears tau in patient-derived neurons and improves motor function in tauopathy mice

Tauopathies are neurodegenerative diseases characterized by pathological tau accumulation, leading to motor and neuropsychiatric symptoms. Effective tau-targeting therapies remain a major challenge, in part because tau lacks well-defined druggable sites and accumulates as heterogeneous intracellular aggregates that are difficult to access and clear. Here, we present 1D9-LIRΔTP53INP2, a single-domain antibody (sdAb)-based protein degrader that facilitates tau clearance through the autophagy-lysosomal pathway. This engineered molecule combines the anti-tau sdAb 1D9 with an LC3-interacting region (LIRΔTP53INP2) to promote autophagosomal recruitment, mimicking autophagy receptors by simultaneously binding tau and LC3. In neurons derived from patients with frontotemporal dementia (FTD) and JNPL3 tauopathy mice, both harboring the P301L tau mutation, 1D9-LIRΔTP53INP2 promoted autophagy-lysosome-mediated tau degradation. It readily crossed the blood-brain barrier and improved motor function in JNPL3 tauopathy mice. These findings underscore the therapeutic potential of sdAb-based protein degraders for tauopathies. Given the challenges of brain delivery for conventional antibodies, sdAbs with enhanced brain penetration and efficacy offer a promising strategy for treatment of neurodegenerative diseases.