From neuroinflammation to immune reprogramming: Nanozyme-Integrated nanoplatforms for neuroimmune modulation in Parkinson's disease

Abstract

Parkinson's disease (PD) is a progressive neuroimmune disorder in which dysregulated neuron–glia–immune crosstalk drives chronic neuroinflammation, α-synuclein pathology, blood–brain barrier dysfunction, and mitochondrial failure, establishing interconnected neuroimmune pathways as therapeutic targets. Aberrant neuron–immune crosstalk promotes chronic neuroinflammation, oxidative stress, mitochondrial dysfunction, blood-brain barrier (BBB) disruption, and α-synuclein pathology, thereby accelerating neurodegeneration. Understanding these interconnected mechanisms has identified multiple neuroimmune pathways as promising therapeutic targets. This review summarizes the cellular and molecular basis of physiological and pathological neuron-immune communication in PD, highlighting the roles of microglial activation, astrocyte reactivity, adaptive immune responses, inflammatory signaling networks, and neurovascular dysfunction. We further discuss emerging neuroimmune-targeted interventions aimed at restoring immune homeostasis and slowing disease progression. Particular emphasis is placed on nanozyme-integrated nanoplatforms that function simultaneously as nanozymatic catalysts and immunomodulatory adjuvants, including enzyme-mimetic nanozymes (SOD/CAT/GPx-like), single-atom catalysts, and nanozyme-integrated nanoplatforms. These platforms not only scavenge reactive oxygen species, degrade α-synuclein aggregates, and reinforce BBB integrity through localized catalytic reactions, but also reprogram innate and adaptive immune responses by modulating microglial polarization toward neuroprotective phenotypes, suppressing pro-inflammatory cytokine cascades (TNF-α, IL-1β, IL-6), and supporting regulatory T cell (Treg) responses. We examine how these nanozyme-integrated nanoplatforms can be combined with lipid-based nanoparticles, polymeric carriers, biomimetic systems, and extracellular vesicles (EVs) to achieve synergistic targeted drug delivery, gene modulation, neuroprotection, and neural repair. Finally, we address the translational challenges and prospects for merging neuroimmunology, nanocatalysis, and adjuvant engineering in PD therapy.