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The marketed topical eye drops for DED treatment often lack bioavailability and precorneal residence time. In this study, we investigated catechol-functionalized polyzwitterion p(MPC-<jats:italic>co<\/jats:italic>-DMA), composed of 2-methacryloyloxyethyl phosphorylcholine (MPC) and dopamine methacrylamide (DMA) monomers, as potential topical nanotherapeutics for DED. The copolymers were synthesized via random free-radical copolymerization, producing different proportions of catecholic functionalization. All as-prepared polymer compositions displayed good ocular biocompatibility. At a feeding ratio of 1:1, p(MPC<jats:sub>1<\/jats:sub>-<jats:italic>co<\/jats:italic>-DMA<jats:sub>1<\/jats:sub>) can facilitate a robust mucoadhesion via Michael addition and\/or Schiff base reaction, thus prolonging ocular residence time after 4 days of topical instillation. The hydration lubrication of MPC and radical-scavenging DMA endow the nano-agent to ease tear-film hyperosmolarity and corneal inflammation. A single dose of p(MPC<jats:sub>1<\/jats:sub>-<jats:italic>co<\/jats:italic>-DMA<jats:sub>1<\/jats:sub>) (1\u00a0mg\/mL) after 4 days post-instillation can protect the cornea against reactive oxygen species, inhibiting cell apoptosis and the over-expression of pro-inflammatory factors (IL-6 and TNF-\u03b1). In clinical assessment, DED-induced rabbit eyes receiving p(MPC<jats:sub>1<\/jats:sub>-<jats:italic>co<\/jats:italic>-DMA<jats:sub>1<\/jats:sub>) could increase lacrimal fluid secretion by 5-fold higher than cyclosporine A. The catechol-functionalized polyzwitterion with enhanced lubricity, mucoadhesion, and anti-oxidation\/anti-inflammation properties has shown high promise as a bioactive eye drop formulation for treating DED.<\/jats:p>","DOI":"10.1186\/s12951-024-02448-x","type":"journal-article","created":{"date-parts":[[2024,4,8]],"date-time":"2024-04-08T08:02:56Z","timestamp":1712563376000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":64,"title":["Mucoadhesive, antioxidant, and lubricant catechol-functionalized poly(phosphobetaine) as biomaterial nanotherapeutics for treating ocular dryness"],"prefix":"10.1186","volume":"22","author":[{"given":"Hoang Linh","family":"Bui","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yun-Han","family":"Su","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chia-Jung","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chun-Jen","family":"Huang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jui-Yang","family":"Lai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,4,8]]},"reference":[{"key":"2448_CR1","doi-asserted-by":"publisher","first-page":"108294","DOI":"10.1016\/j.exer.2020.108294","volume":"201","author":"VL Perez","year":"2020","unstructured":"Perez VL, Stern ME, Pflugfelder SC. 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