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DNA Scaffolds Enable Efficient and Tunable Functionalization of Biomaterials for Immune Cell Modulation

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DNA Scaffolds Enable Efficient and Tunable Functionalization of Biomaterials for Immune Cell Modulation ARTICLES https://doi.org/10.1038/s41565-020-00813-z DNA scaffolds enable efficient and tunable functionalization of biomaterials for immune cell modulation Xiao Huang 1,2, Jasper Z. Williams 2,3, Ryan Chang1, Zhongbo Li1, Cassandra E. Burnett4, Rogelio Hernandez-Lopez2,3, Initha Setiady1, Eric Gai1, David M. Patterson5, Wei Yu2,3, Kole T. Roybal2,4, Wendell A. Lim2,3 ✉ and Tejal A. Desai 1,2 ✉ Biomaterials can improve the safety and presentation of therapeutic agents for effective immunotherapy, and a high level of control over surface functionalization is essential for immune cell modulation. Here, we developed biocompatible immune cell-engaging particles (ICEp) that use synthetic short DNA as scaffolds for efficient and tunable protein loading. To improve the safety of chimeric antigen receptor (CAR) T cell therapies, micrometre-sized ICEp were injected intratumorally to present a priming signal for systemically administered AND-gate CAR-T cells. Locally retained ICEp presenting a high density of priming antigens activated CAR T cells, driving local tumour clearance while sparing uninjected tumours in immunodeficient mice. The ratiometric control of costimulatory ligands (anti-CD3 and anti-CD28 antibodies) and the surface presentation of a cytokine (IL-2) on ICEp were shown to substantially impact human primary T cell activation phenotypes. This modular and versatile bio- material functionalization platform can provide new opportunities for immunotherapies. mmune cell therapies have shown great potential for cancer the specific antibody27, and therefore a high and controllable den- treatment, but still face major challenges of efficacy and safety sity of surface biomolecules could allow for precise control of ligand for therapeutic applications1–3, for example, chimeric antigen binding and cell modulation. I 4 receptor (CAR) T cell treatment for a broad range of patients and Currently, there is an unmet need for robust and biocompatible solid tumours5–9. Immunomodulatory signals, including costimu- conjugation strategies to functionalize the surface of biodegrad- latory ligands10, cytokines11–13 and checkpoint inhibitors14, have able materials with biomolecules (particularly proteins/antibodies) been used extensively to boost immune cell activity and modulate at high densities and to present multiple moieties at precisely con- tumour environment for improved efficacy1,3. Synthetic biocompat- trolled ratios28–30. Polyethylene glycol (PEG) is commonly used as a ible materials have been employed as carriers for these biomolecules linker or scaffold for bioconjugation29, but this method is limited by to facilitate specific localization and prolonged stability in vivo, for inefficient presentation of functional groups due to the flexibility the modulation of natural or engineered immune cell activities15–19. of PEG31. The surface functionalization of multiple biomolecules To increase tumour-targeting specificity and avoid ‘on-target, and their ratiometric control mostly rely on streptavidin-based off-tumour’ toxicity in bystander healthy tissues, CAR T cells have chemistry32 or orthogonal conjugation strategies33, which can be been engineered with combinatorial antigen AND-gate activation substantially affected by the chemical properties of the specific car- control that requires sensing two antigens on a target cell, a priming gos. Oligonucleotides have been used as building blocks for origami antigen to activate CAR expression and a second antigen to initiate structures with a controlled display of proteins34,35 and as surface scaf- target killing20,21. The clinical application of this approach, however, folds on metallic particles for short interfering RNA delivery31,36,37, requires knowledge about factors that control T-cell activity, such but have yet to be fully utilized for modular and multimodal protein as the tumour-associated antigen density of the AND-gate prim- assembly on biodegradable materials38. Synthetic short oligonucle- ing or CAR-targeting antigens2. An understanding of the density otides—natural polymers with a controllable sequence and unique dependence of antigen-modulated T-cell activation is important assembly through Watson–Crick base pairing35,39—would be ideal for therapeutic optimization. Biomaterials presenting the prim- mediators for controlled surface functionalization of biomolecules. ing signal (natural or synthetic antigen) at a desired density for Here, we developed short synthetic DNA scaffolds for the localized activation of such engineered T cells would mitigate the functionalization of biomolecules on the surface of biodegradable safety concerns of the dual-antigen design2,21 for translational use. particles to extend the immunomodulatory potential (Fig. 1a). Additionally, synthetic materials with multivalent and multimodal For our demonstration platform, we fabricated micrometre-sized biofunctionalization could advance the needs of cell modulation immune cell-engaging particles (ICEp) using a biocompat- in immunotherapies22–26. Antibody–antigen binding on surfaces ible poly(lactic-co-glycolic acid) (PLGA) polymer40. DNA strands requires a certain spatial threshold based on the spatial tolerance of were immobilized on the surface of polymeric particles through 1Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, CA, USA. 2Cell Design Institute and Center for Synthetic Immunology, University of California, San Francisco, San Francisco, CA, USA. 3Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA, USA. 4Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, CA, USA. 5Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, CA, USA. ✉e-mail: wendell.lim@ ucsf.edu; [email protected] NatURE NANOtechnOLOgy | www.nature.com/naturenanotechnology ARTICLES NATURE NANOTECHNOLOGY an emulsion protocol to create an adaptable scaffold for load- To accommodate diverse applications, from intracellular payload ing bioactive molecules (Supplementary Fig. 1a). Polymer–DNA delivery to extracellular signal transduction, DNA-scaffolded par- amphiphilic molecules were synthesized with optimizations, ticles can be synthesized at various sizes and loaded with biomol- including the choice of the polymer, DNA length, solvent and ecules in their core. Particle size can be controlled by tuning key reaction conditions, to form stable PLGA particles with dense emulsion parameters (Supplementary Fig. 2k,l). Additionally, the DNA scaffolds (Supplementary Fig. 1b–f). The direct incorpora- core of these particles can be loaded with biomolecules, including tion of the reaction mixtures with increasing yield of polymer– oligonucleotides and peptides, through a double-emulsion protocol DNA conjugate (from varying ratios of thiol-modified DNA to (Supplementary Fig. 2m–o). PLGA10k-PEG5k-maleimide) into the emulsion protocol yielded a continuous increase of surface payload-attachable DNA scaf- Highly efficient loading of multiple proteins with fold density (Fig. 1b,c and Supplementary Fig. 1d). Strikingly, ratiometric control the highest average surface loading density on particles (~5 mil- Biomolecules can be loaded onto the surface of DNA-scaffolded par- lion DNA duplexes per particle, Supplementary Fig. 1g–i) was ticles using one of two strategies: (1) through a surface step-by-step roughly analogous to the theoretical limit (at ~4 million by foot- conjugation via a bifunctional linker; and (2) through direct print calculation, based on ~2 nm diameter of the DNA duplex) hybridization of complementary DNA–biomolecule conjugates to of a spherical particle with a diameter of 2 μm. In particular, this the scaffold (Fig. 2a). In the case of a fluorescently labelled human hybridization-guided loading was about 27-fold more efficient than IgG, surface step-by-step conjugation saturated the protein loading, loading from a traditional method41, in which surface-exposed even with increased densities of available DNA linkers on the sur- maleimide groups, after particle fabrication using an equal amount face (Figs. 1c and 2b and Supplementary Fig. 3a). In contrast, the of PLGA10k-PEG5k-maleimide, were reacted with thiol-modified hybridization-guided assembly strategy showed an approximately DNA molecules (Fig. 1b,c). This hybridization-guided assembly threefold higher level of IgG loading than the surface-conjugation protocol is biocompatible, convenient and rapid, such that incuba- method for particles with denser DNA scaffolds (P = 0.0002), and tion at room temperature for 2 min achieved ~87% of the maximum the increase in IgG loading corresponded to the increase in scaffold loading (Fig. 1d and Supplementary Fig. 1j-l). density (Fig. 2b). The highest level of IgG loading achieved (at ~0.6 Furthermore, using unique DNA nucleotide sequences enables million per particle) was again comparable to the theoretical foot- independent control of loading multiple cargos on the same mate- print limit of a spherical particle at 2 μm in diameter (~0.64 million rial surface (Fig. 1e). Polymer–DNA conjugates with three dis- per particle, based on ~5-nm diameter of IgG) (Fig. 2b). To gen- tinct DNA sequences (namely R, G and B strands, Supplementary erate DNA–antibody conjugates with minimal impact on antibody Fig. 2a) were incorporated into the particle emulsion with reac- activity, a ‘TCEP’ strategy42 was chosen, whereby the antibody hinge tion
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