Rapid <i>in situ</i> forming PEG hydrogels for mucosal drug delivery

<i>In situ</i> gelling polymeric biomaterials have proven useful as drug delivery vehicles to enable sustained release at the sites of disease or injury. However, if delivered to mucosal tissues, such as the eyes, nose, and gastrointestinal and cervicovaginal tracts, these gels must also possess the ability to adhere to an epithelium coated in mucus. Towards this end, we report a new rapid <i>in situ</i> gelling polyethylene glycol-based hydrogel. Unlike other chemistries that enable rapid gel formation <i>via</i> irreversible covalent bonds, we use a bio-reducible linker allowing the gels to be naturally degraded over several days once administered. We identified a set of 6 lead formulations, which rapidly transform into disulfide-linked PEG hydrogels in 30 seconds or less. These rapidly forming PEG hydrogels were also able to conform and adhere to mucosal tissues <i>via</i> PEG-mucin entanglements and hydrogen bonding. Controlled release of protein-based cargoes from the PEG gels was achieved over several hours, whereas 40 nm nanoparticle-based cargos were retained over 24 hours. We also found that these rapid <i>in situ</i> forming PEG gels were well tolerated by mammalian cells and were retained in the nasal cavity of mice for up to 1 week. These studies support further testing and development of rapid <i>in situ</i> forming PEG gels for drug delivery to improve therapeutic retention and efficacy at mucosal sites.