A novel biomacromolecule-predominated hybrid unit: from design, characterization to application

ABSTRACT Current biomaterial designs struggle with complex clinical and life science demands as single-function approaches are increasingly inadequate, necessitating the systematic integration of four core elements: biosafety, physiological compatibility, biomechanical matching, and biocatalytic function across hierarchical levels. This study addresses the challenge by introducing a novel strategy using natural biomacromolecules to construct microscopic organic-inorganic hybrid units. A comprehensive characterization paradigm employing synchrotron small-angle X-ray scattering, atomic force microscopy coupled with infrared spectroscopy and high-resolution transmission electron microscope was established to reveal emergent hybrid properties. Systematic characterization results demonstrate that the physicochemical properties of these hybrid units more closely resemble polymers than traditional nanomaterials. We introduced the classical polymer blob model to reveal the effects of the hybridization process on the rigidity/flexibility of the polymer chains. Combined characterization results confirmed that the hybrid units possess stable interfaces, bioinspired crosslinking, synergistic high enzyme-like activity with low toxicity, and broad pH tolerance. Multifunctional nanohybrid hydrogel, fabricated with these hybrid units, significantly enhances mammalian cell synthesis of high-quality PD-L1 protein with efficiency improved by nearly an order of magnitude and effectively protects skin organoids from damage caused by exogenous reactive oxygen species. Integrated multi-omics analysis demonstrates that the hydrogel modulates cell–cell/matrix interactions via mechano-bioinspiration, boosts endoplasmic reticulum protein processing, and ameliorates hypoxia to enhance mitochondrial respiration (without active oxygen supply), achieving systematic integration of biocompatibility, biomechanics, biocatalysis and physiological environment compatibility. The study also demonstrates the potential of hybrid units in applications such as hydrogel-derived optical fiber fabrication, 3D bio-printing and in vitro advanced cell culture models.