A Click-Based Strategy to Customize Polymer–Nanoparticle Hydrogel Properties for Versatile Biomedical Applications

Polymer–nanoparticle (PNP) hydrogels consist of a unique type of water-rich polymer network formed by dynamic, supramolecular bridging interactions between polymers and nanoparticles. Previous work by Appel and colleagues has demonstrated that dodecyl-modified hydroxymethylcellulose (C12-HPMC) can form supramolecular hydrophobic interactions with poly(ethylene glycol)-<i>b</i>-poly(lactic acid) nanoparticles (PEG-PLA NPs), providing injectable hydrogels well-suited for the sustained delivery of pharmaceuticals and cell-based therapies. Although other polymer–nanoparticle pairs have been investigated, including hexyl- and adamantyl-modified HPMC or various block copolymer nanoparticles, tuning PNP properties has largely been limited to altering the concentration of C12-HPMC and PEG-PLA NPs in solution. Thus, "stiff" PNP hydrogels are often prepared by mixing 2 wt% C12-HPMC with 10 wt% PEG-PLA NPs, while "soft" hydrogels will be prepared by mixing 1 wt% and 5 wt%, respectively. Although much successful work has been demonstrated by this simple concentration-based method, strategies to independently modulate concentrations, polymer–nanoparticle interactions, and hydrogel mechanics would enable better customization for broad biomedical applications.<br/><br/>Previous methods to prepare PNP hydrogel derivatives have been limited by the arduous synthetic requirements of block copolymer libraries or the limited scope of the reported HPMC modification strategy. Here, we leverage a robust click reaction that is compatible with a multitude of commercially available thiols and cysteine-bearing peptides to prepare a library of modified HPMC derivatives. We will demonstrate how systematically altering the hydrophobic or steric character of modifications can be used to tailor the mechanical properties of subsequent PNP hydrogels and how those mechanical properties relate to cell compatibility, hydrogel lifetime, and drug retention <i>in vivo</i>. We will also highlight how this strategy can be used to incorporate bioactive moieties within the PNP system to optimize cellular interactions. This ongoing work offers a route to optimize PNP hydrogels for a variety of translational applications and holds particular promise in the highly tunable delivery of pharmaceuticals and adoptive cells.