Mucus‐Inspired Self‐Healing Hydrogels: A Protective Barrier for Cells against Viral Infection

Abstract Mucus is a dynamic biological hydrogel, composed primarily of the glycoprotein mucin, exhibits unique biophysical properties and forms a barrier protecting cells against a broad‐spectrum of viruses. Here, this work develops a polyglycerol sulfate‐based dendronized mucin‐inspired copolymer ( MICP‐1 ) with ≈10% repeating units of activated disulfide as cross‐linking sites. Cryo‐electron microscopy (Cryo‐EM) analysis of MICP‐1 reveals an elongated single‐chain fiber morphology. MICP‐1 shows potential inhibitory activity against many viruses such as herpes simplex virus 1 (HSV‐1) and SARS‐CoV‐2 (including variants such as Delta and Omicron). MICP‐1 produces hydrogels with viscoelastic properties similar to healthy human sputum and with tuneable microstructures using linear and branched polyethylene glycol‐thiol (PEG‐thiol) as cross‐linkers. Single particle tracking microrheology, electron paramagnetic resonance (EPR) and cryo‐scanning electron microscopy (Cryo‐SEM) are used to characterize the network structures. The synthesized hydrogels exhibit self‐healing properties, along with viscoelastic properties that are tuneable through reduction. A transwell assay is used to investigate the hydrogel's protective properties against viral infection against HSV‐1. Live‐cell microscopy confirms that these hydrogels can protect underlying cells from infection by trapping the virus, due to both network morphology and anionic multivalent effects. Overall, this novel mucin‐inspired copolymer generates mucus‐mimetic hydrogels on a multi‐gram scale. These hydrogels can be used as models for disulfide‐rich airway mucus research, and as biomaterials.