RT Journal Article SR Electronic T1 A thiol–ene click-based strategy to customize injectable polymer–nanoparticle hydrogel properties for therapeutic delivery JF bioRxiv FD Cold Spring Harbor Laboratory SP 2024.09.13.612978 DO 10.1101/2024.09.13.612978 A1 Bailey, Sophia J. A1 Eckman, Noah A1 Brunel, Elisa S. A1 Jons, Carolyn K. A1 Sen, Samya A1 Appel, Eric A. YR 2024 UL http://biorxiv.org/content/early/2024/09/19/2024.09.13.612978.abstract AB Polymer–nanoparticle (PNP) hydrogels are a promising injectable biomaterial platform that has been used for a wide range of biomedical applications including adhesion prevention, adoptive cell delivery, and controlled drug release. By tuning the chemical, mechanical, and erosion properties of injected hydrogel depots, additional control over cell compatibility and pharmaceutical release kinetics may be realized. Here, we employ thiol–ene click chemistry to prepare a library of modified hydroxypropylmethylcellulose (HPMC) derivatives for subsequent use in PNP hydrogel applications. When combined with poly(ethylene glycol)-b-poly(lactic acid) nanoparticles, we demonstrate that systematically altering the hydrophobic, steric, or pi stacking character of HPMC modifications can readily tailor the mechanical properties of PNP hydrogels. Additionally, we highlight the compatibility of the synthetic platform for the incorporation of cysteine-bearing peptides to access PNP hydrogels with improved bioactivity. Finally, through leveraging the tunable physical properties afforded by this method, we show hydrogel retention time in vivo can be dramatically altered without sacrificing mesh size or cargo diffusion rates. This work offers a route to optimize PNP hydrogels for a variety of translational applications and holds promise in the highly tunable delivery of pharmaceuticals and adoptive cells.Competing Interest StatementThe authors have declared no competing interest.