Reverse the progression of Alzheimer's disease through Nano-ERASER-based adult neuroregeneration.

Alzheimer's disease (AD) remains irreversible largely because the adult brain cannot replace lost neurons. Here, we present a Nano-ERASER-based Trim-Away system (TN-PTBP1) that enables adult neuroregeneration in the AD brain, offering a new strategy to counteract AD progression. TN-PTBP1 penetrates the blood-brain barrier, delivers anti-PTBP1 antibodies into astrocytes, and triggers rapid TRIM21-mediated PTBP1 degradation. This non-genomic protein depletion induces astrocyte-to-neuron conversion, generates functional neurons in vitro and in human brain organoids, and restores hippocampal neurogenesis in AD mice. Importantly, TN-PTBP1 treatment significantly improves cognition, learning, and memory, demonstrating true functional reversal of AD-associated deficits. By resolving the long-standing controversy surrounding PTBP1 reprogramming and establishing a translational biomaterials-based platform for in situ neuronal regeneration, this work introduces a transformative therapeutic paradigm aimed not only at slowing AD but at rebuilding the neuronal circuitry it destroys.