Advances of targeted protein degradation strategies for precision therapy of neurodegenerative diseases

Neurodegenerative diseases (NDDs) are marked by disruptions in protein homeostasis, including abnormal synthesis, misfolding, aggregation, and defective degradation of pathogenic proteins, leading to neurotoxicity. In recent years, multilayered therapeutic strategies targeting protein homeostasis have been developed, such as transcriptional and translational regulation, conformational stabilization, aggregation inhibition, and protein clearance approaches represented by targeted protein degradation (TPD). Since the pathological lesions of NDDs are primarily located in the central nervous system, effective interventions require that therapeutic agents cross the blood-brain barrier (BBB) and be precisely delivered to diseased brain regions. This review systematically summarizes the pathogenic mechanisms underlying protein homeostasis imbalance in NDDs and highlights current therapeutic strategies, with an emphasis on recent advances and therapeutic potential of TPD approaches. We further overview various brain-targeted nanodelivery systems, including those responsive to the brain microenvironment and capable of targeting specific cells and subcellular organelles, which collectively enable precise trans-BBB delivery and intracellular targeting. These advances support the development of precision therapies aimed at restoring protein homeostasis. This review provides insights into the progress of brain-targeted TPD technologies and their supporting nanodelivery strategies.