Molecular design of phosphatidylserine-inspired polymers for efficient anti-inflammatory therapy via enhanced interaction with Tim-4

Kosuke Sato; Ahmed Nabil; Komol Kanta Sharker; Kouichi Shiraishi; Mitsuhiro Ebara

doi:10.1038/s41428-025-01140-7

Article Molecular design of phosphatidylserine-inspired polymers for efficient anti-inflammatory therapy via enhanced interaction with Tim-4

Kosuke Sato (National Institute for Materials Science) ; Ahmed Nabil ; Komol Kanta Sharker ; Kouichi Shiraishi ; Mitsuhiro Ebara (National Institute for Materials Science)

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Kosuke Sato, Ahmed Nabil, Komol Kanta Sharker, Kouichi Shiraishi, Mitsuhiro Ebara. Molecular design of phosphatidylserine-inspired polymers for efficient anti-inflammatory therapy via enhanced interaction with Tim-4. Polymer Journal. 2026, (), 407-415. https://doi.org/10.1038/s41428-025-01140-7

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This study investigated the interaction between phosphatidylserine (PS)-inspired polymers　and T cell immunoglobulin and mucin-like domain-containing protein 4 (Tim-4) by systematically varying the monomer structure and copolymer composition. A series of alkyl-substituted PS-inspired monomers was synthesized using a modified phosphoramidite method, and well-defined homopolymers and 2-hydroxyethyl methacrylate (HEMA)-containing copolymers were prepared via reversible addition–fragmentation chain-transfer polymerization. Structural analyses using 1H nuclear magnetic resonance and gel permeation chromatography confirmed the successful synthesis with controlled molecular weights. Biolayer interferometry was used to quantify Tim-4 binding, revealing a non-monotonic effect of alkyl substitution, whereas the incorporation of HEMA consistently enhanced Tim-4 binding in a composition-dependent manner. Biological evaluation using RAW-Blue macrophages showed that the homopolymers did not significantly affect interleukin-6 (IL-6) secretion, whereas the copolymers selectively suppressed IL-6 production. Notably, the copolymer containing 50 mol% PS units exhibited the strongest IL-6 suppression, and the HEMA-containing copolymers exhibited anti-inflammatory activity even at lower PS concentrations than the homopolymers. These results demonstrate that copolymer composition critically influences receptor interactions and immune modulation. This study highlights the potential of PS-inspired copolymers as biomaterials that mimic apoptotic cell signals and exert efficient anti-inflammatory effects through an optimized molecular design.

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