Injectable Polymeric Cytokine-Binding Nanowires Are Effective Tissue-Specific Immunomodulators

Abstract

Injectable nanomaterials that interact with the host immune system without surgical intervention present spatially anchored complements to cell transplantation and could offer improved pharmacokinetics compared to systemic cytokine therapy. Here we demonstrate fabrication of high aspect ratio polycaprolactone nanowires coupled with cytokine-binding antibodies that assemble into porous matrices when injected into the subcutaneous space. These structures are fabricated using a nanotemplating technique that allows for tunability of particle dimensions and utilize a straightforward maleimide conjugation chemistry to allow site-specific coupling to proteins. Nanowires are well tolerated in vivo and incite minimal inflammatory infiltrate. Nanowires conjugated with antibodies were designed to capture and potentiate endogenous interleukin-2 (IL-2), an important leukocyte activating cytokine. Together these nanowire-antibody matrices were capable of localizing endogenous IL-2 in the skin and activated targeted specific natural killer and T cell subsets, demonstrating both tissue- and cell-specific immune activation. These self-assembling nanowire matrices show promise as scaffolds to present engineered, local receptor–ligand interactions for cytokine-mediated disease.

Bioinspired Polymeric High‐Aspect‐Ratio Particles with Asymmetric Janus Functionalities

“…[ 30 ] Thus, when fabricating HARPs, we have previously observed particles with 200 nm diameters even when HARP formation is initiated at the 20 nm side of the AAO template. [ 27 ] This is due to extended templating times of 2–3 h, which provide sufficient time for PCL to pass through the 20 nm branched porous region of the Anodiscs. We therefore hypothesized that if a limited templating occurs, PCL polymers would be retained partially within the 20 nm branching porous region of the AAO template ( Figure 1 a).…”

DNA-scaffolded biomaterials enable modular and tunable control of cell-based cancer immunotherapies

“…Through this highly modular platform, biocompatible materials can be employed as substrates for a wide spectrum of modulatory biomolecules, including cytokines 5 , antigens 10 , checkpoint inhibitors 43 , agonistic or antagonistic antibodies 44 , adjuvants 9, 11 , etc., to regulate the local environment and enhance the efficacy of immune cells in cancer immunotherapy 8 . Synthetic materials with tunable properties can enhance the pharmacokinetics of regulatory biomolecules in vivo 1,6,8 , and sometimes provide a necessary surface substrate for biomolecules to activate the cognate cell signaling 10,25,28 . Biomaterials fabricated with controlled size, shape, and composition -for example, microspheres, nanowires, and porous scaffolds -can also serve as a local adjuvant 2, 3, 7, 13 for biomolecules or engineered immune cells to exert tumor targeted toxicity without systemic diffusion, thus minimizing the off-target side effects.…”

“…AICE injected intratumorally can provide a local priming signal for systemically administered AND-gate chimeric antigen receptor T cells, driving local tumor clearance while sparing uninjected tumors that model potentially cross-reactive healthy tissues. This modularly functionalized biomaterial thus provides a flexible platform to achieve sophisticated control over cell-based immunotherapies.Functionalized biomaterials can work synergistically with natural or engineered immune cells for cancer immunotherapy [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15] . Adoptive cell therapy (ACT) using chimeric antigen receptor (CAR) engineered T cells has shown success and clinical approval for the treatment of B cell cancers 16 .…”

“…Biomaterials functionalized with modulatory biomolecules at pre-specified densities have been shown to communicate with and control therapeutic immune cells both ex vivo and in vivo [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15] . For example, synthetic materials have been functionalized with agonistic antibodies for CD3 and CD28 to drive ex vivo T cell expansion 25,26 .…”

Maleimidophenyl isocyanates as postpolymerization modification agents and their applications in the synthesis of block copolymers

“…The easy introduction of maleimide moieties in common polymer chains, that is, those easily synthesized or commercially available, would provide powerful scaffolds and building blocks for the rapid construction of macromonomers and block copolymers. For that purpose, we focused our attention on p ‐maleimidophenyl isocyanate ( PMPI ) [Fig. (a)] as a modification agent, which can be used to directly transform the hydroxy groups in polymer chains into reactive maleimide groups via a one‐pot reaction with the reactive isocyanate group.…”