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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\u2010target therapeutic strategies. Moreover, cell\u2010free DNA (cfDNA)\u2014an emerging inflammatory mediator\u2014has 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)\u2010modified CuInP\n                    <jats:sub>2<\/jats:sub>\n                    S\n                    <jats:sub>6<\/jats:sub>\n                    (CIPS) nanosheets (C\u2010TA\n                    <jats:sub>1<\/jats:sub>\n                    ; w\/w = 1:1) as a multi\u2010targeting therapeutic nanoplatform for recalcitrant airway inflammatory diseases. The C\u2010TA\n                    <jats:sub>1<\/jats:sub>\n                    nanosheets demonstrated efficient cfDNA clearance via hydrogen bonding interactions, thereby inhibiting cfDNA\u2010triggered toll\u2010like receptor 9 (TLR9) activation and subsequent nuclear factor\u2010\u03baB (NF\u2010\u03baB) inflammatory signaling. Additionally, C\u2010TA\n                    <jats:sub>1<\/jats:sub>\n                    exhibited potent antioxidant and antibacterial activities, which were ascribed to the inherent properties of the two\u2010dimensional nanostructure and the chemical characteristics of TA, respectively. The in vivo therapeutic efficacy of C\u2010TA\n                    <jats:sub>1<\/jats:sub>\n                    was evaluated in murine models with neutrophilic and eosinophilic airway inflammation, respectively. C\u2010TA\n                    <jats:sub>1<\/jats:sub>\n                    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\u2011inflammatory cytokines. Furthermore, treatment with C\u2010TA\n                    <jats:sub>1<\/jats:sub>\n                    effectively modulated the dysregulated airway microbiota observed in the inflammatory state. Our findings demonstrate a multi\u2010targeting 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\u2010related diseases.\n                  <\/jats:p>","DOI":"10.1002\/exp.20250073","type":"journal-article","created":{"date-parts":[[2026,3,13]],"date-time":"2026-03-13T04:30:58Z","timestamp":1773376258000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Surmounting Recalcitrant Airway Inflammatory Disorders With a Multi\u2010Targeting Therapeutic Strategy by Tannic Acid\u2010Modified CuInP\n                    <sub>2<\/sub>\n                    S\n                    <sub>6<\/sub>\n                    Nanosheets"],"prefix":"10.1002","volume":"6","author":[{"given":"Ming","family":"Liu","sequence":"first","affiliation":[{"name":"Department of Otolaryngology The Sixth Affiliated Hospital Sun Yat\u2010sen University  Guangzhou China"},{"name":"Biomedical Innovation Center The Sixth 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Sun Yat\u2010sen University  Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhaofeng","family":"Xu","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology The First Affiliated Hospital Sun Yat\u2010sen University  Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuaiyin","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology The Sixth Affiliated Hospital Sun Yat\u2010sen University  Guangzhou China"},{"name":"Biomedical Innovation Center The Sixth Affiliated Hospital Sun Yat\u2010sen University  Guangzhou China"},{"name":"Key Laboratory of Human Microbiome and Chronic Diseases Ministry of Education Sun Yat\u2010sen University  Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jian","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology The First Affiliated Hospital Sun Yat\u2010sen University  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