Genetically Encoded Interpenetrating Polymer Networks as Injectable Biomaterials for Controlled Therapeutic Protein Delivery

Though recombinant protein therapeutics hold great potential in treating many diseases, their intravenous delivery introduces challenges with off-target effects and short circulation half-lives. Injectable biomaterial depots have proven useful in confining therapeutic administration to specific bodily locations but have faced difficulties in simultaneously controlling drug release, network mechanics, and functionalization. Toward addressing these limitations, this work introduces the first recombinant protein-based interpenetrating polymer network (IPN), which we exploit for injectable therapeutic deposition. Each of the self-sorting telechelic biopolymer networks is comprised of an intrinsically disordered XTEN protein midblock differentially flanked with one of two orthogonally self-assembling coil domains that enable rapid shear-thinning and self-healing responsiveness in biomaterials with tunable viscoelasticity. Exploiting the orthogonal and genetically encoded click-like SpyLigation/SnoopLigation chemistries to independently tether proteins-of-interest to each underlying network, we demonstrate that fluorescent proteins and growth factors (rhIGF-1, rhEGF) can be released in a controlled fashion from materials with tunable viscoelasticity while retaining high bioactivity following network dissolution. Such recombinant IPN biomaterials offer exciting opportunities for next-generation biotherapeutic delivery.