Disrupting neuro-immune crosstalk through cfDNA/NETs degradation by Zr4+-based nanoenzymes: A therapeutic strategy for airway inflammatory disorders.

Recent studies have established that neuro-immune interactions are essential for the pathogenesis and persistence of airway inflammation. In line with this, our work demonstrates that neutrophil extracellular traps (NETs) stimulate neuropeptide secretion-a finding corroborated by elevated neuropeptide levels in nasal polyps from patients with chronic rhinosinusitis with nasal polyps (CRSwNP) and in corresponding murine models. Current nano-scavengers, which primarily rely on electrostatic adsorption to immobilize cell-free DNA (cfDNA)/NETs, face practical limitations, including susceptibility to competing polyanions, limited adsorption capacity, and poor stability. To overcome these drawbacks, we synthesized a class of nanozymes based on high-valent metal ions (Zr4+ or Ce4+) coordinated with three distinct organic ligands. These nanozymes exhibited robust catalytic degradation of cfDNA/NETs, with Zr4+-based variants showing the highest efficacy-highlighting the importance of rational metal-ion and ligand selection in designing effective anti-inflammatory nanomedicines. In murine models of ovalbumin (OVA)- or lipopolysaccharide (LPS)-induced airway inflammation, intranasal administration of Zr4+-based nanozymes significantly reduced cfDNA/NETs levels in inflammatory tissues and decreased total inflammatory-cell counts. Importantly, by degrading cfDNA/NETs, these nanozymes also attenuated neuropeptide release from airway sensory neurons and neuroendocrine cells, thereby suppressing neuro-immune amplification and airway hyperresponsiveness. In summary, our study underscores the importance of a strategically engineered composition for constructing nanozymes capable of efficiently degrading cfDNA/NETs. By simultaneously dismantling the cfDNA/NETs scaffold and disrupting neuropeptide-mediated feed-forward inflammatory loops, these agents offer a dual-mode precision nanomedicine strategy for the treatment of airway inflammatory diseases.