Surmounting Recalcitrant Airway Inflammatory Disorders With a Multi‐Targeting Therapeutic Strategy by Tannic Acid‐Modified CuInP ₂ S ₆ Nanosheets

ABSTRACT Recalcitrant airway inflammatory diseases have drawn significant attention due to their high incidence and substantial healthcare costs. Analysis of clinical samples from patients with chronic rhinosinusitis with nasal polyps (CRSwNP) revealed the coexistence of neutrophilic and eosinophilic inflammation, which may account for the limited efficacy of traditional single‐target therapeutic strategies. Moreover, cell‐free DNA (cfDNA)—an emerging inflammatory mediator—has been implicated in both eosinophilic and neutrophilic responses through its role in the formation of extracellular traps. In this study, we developed tannic acid (TA)‐modified CuInP 2 S 6 (CIPS) nanosheets (C‐TA 1 ; w/w = 1:1) as a multi‐targeting therapeutic nanoplatform for recalcitrant airway inflammatory diseases. The C‐TA 1 nanosheets demonstrated efficient cfDNA clearance via hydrogen bonding interactions, thereby inhibiting cfDNA‐triggered toll‐like receptor 9 (TLR9) activation and subsequent nuclear factor‐κB (NF‐κB) inflammatory signaling. Additionally, C‐TA 1 exhibited potent antioxidant and antibacterial activities, which were ascribed to the inherent properties of the two‐dimensional nanostructure and the chemical characteristics of TA, respectively. The in vivo therapeutic efficacy of C‐TA 1 was evaluated in murine models with neutrophilic and eosinophilic airway inflammation, respectively. C‐TA 1 markedly attenuated airway inflammation in both of these animal models by reducing reactive species, immune cell infiltration, goblet cell hyperplasia and the expression of pro‑inflammatory cytokines. Furthermore, treatment with C‐TA 1 effectively modulated the dysregulated airway microbiota observed in the inflammatory state. Our findings demonstrate a multi‐targeting nanoformulation designed to mitigate multiple key pathological drivers of severe airway inflammation concurrently. This engineered system presents a promising strategy for managing respiratory inflammatory disorders and also other inflammation‐related diseases.