Nanogels crosslinked with a novel selenocystine-based linker for triple-stimuli-responsive drug delivery

• First water-processable nanogel crosslinked with a new selenium-based BISeSe linker • BISeSe enables triple-responsiveness (GSH, pH, temperature) without extra comonomers • Surfactant-free, aqueous synthesis yields uniform 60 nm particles (PDI = 0.05, DLS) • Tumour-mimicking conditions trigger fast and selective DOX release • DOX-nanogel 60 × less toxic to healthy cells and 1.6 × more potent vs MCF-7 than free drug A first-in-class, water-processable nanogel was obtained by surfactant-free semi-batch precipitation polymerisation of poly(N-isopropylacrylamide) (pNIPA) cross-linked with the new selenium linker N,N′-bis(acryloyl)selenocystine (BISeSe). Unlike conventional disulfide, diselenide or acid-cleavable linkers, BISeSe delivers (1) carboxyl groups that impart pH-responsiveness and (2) Se-Se bonds that undergo glutathione reduction, thus merging two key intracellular triggers in a single, predominantly aqueous, surfactant-free polymerisation process that avoids organic solvents during nanogel formation and requires no post-synthetic modifications.. The process yields highly monodisperse spheres (60 ± 6 nm, TEM; PDI= 0.05, DLS) with an overall yield of 82%.. Doxorubicin (DOX) is electrostatically loaded at 25 wt % with 81 % efficiency. At pH 7.4 without GSH, nanogels release only 13.9 % of DOX after 12 h, whereas at pH 5.0 with 10 mM GSH they discharge 84 % in the same period, following an erosion-dominated Korsmeyer-Peppas profile (n = 0.53). Blank carriers retain ≥ 80 % viability in MCF-7 and MCF-10A cells, while DOX-loaded gels are 1.6-fold more potent than free DOX against MCF-7 and ∼60-fold less toxic to MCF-10A (IC₅₀ 0.08 vs 9.65 µM). This water-based polymerisation route provides a scalable and cleaner alternative to conventional organic-phase syntheses, offering a promising platform for selective drug-delivery systems.