Targeting the NLRP3 inflammasome with antibody-based therapeutics for chronic neurodegenerative diseases

The NLRP3 inflammasome is a central regulator of innate immunity that becomes aberrantly activated by amyloid-β, hyperphosphorylated tau, and α-synuclein aggregates in chronic neurodegenerative diseases, such as Alzheimer's (AD) and Parkinson's disease (PD). Sustained activation drives neuroinflammation, synaptic dysfunction, and neuronal loss, making NLRP3 a compelling therapeutic target.

This review summarizes current insights into NLRP3 inflammasome biology in AD and PD, with emphasis on antibody-based interventions. Emerging delivery approaches, such as receptor-mediated transcytosis, nanoparticles, adeno-associated viral vectors, and magnetic resonance-guided focused ultrasound are also examined for their potential to enhance central nervous system (CNS) delivery of NLRP3-targeting antibodies.

Antibody-based NLRP3 inhibitors offer high specificity and favorable safety profile compared with small-molecular-weight inhibitors; however, limited blood-brain barrier (BBB) penetration remains a major challenge. Advances in antibody engineering, modular bi-/multi-specific designs, and targeted CNS delivery platforms may soon enable the development of first-in-class antibodies capable of directly modulating neuroinflammation. To realize this potential, the field should prioritize: (1) developing BBB-penetrant antibody constructs; (2) integrating delivery technologies with target biology; and (3) accelerating translation toward first-in-human studies. Successful implementation could transform therapeutic strategies for AD and PD and extend antibody-based interventions across a broader spectrum of neuroinflammatory disorders.