Adoptive cell therapy (ACT) with antigen-specific T cells has shown remarkable clinical success; however, approaches to safely and effectively augment T cell function, especially in solid tumors, remain of great interest. Here we describe a strategy to 'backpack' large quantities of supporting protein drugs on T cells by using protein nanogels (NGs) that selectively release these cargos in response to T cell receptor activation. We designed cell surface-conjugated NGs that responded to an increase in T cell surface reduction potential after antigen recognition and limited drug release to sites of antigen encounter, such as the tumor microenvironment. By using NGs that carried an interleukin-15 super-agonist complex, we demonstrated that, relative to systemic administration of free cytokines, NG delivery selectively expanded T cells 16-fold in tumors and allowed at least eightfold higher doses of cytokine to be administered without toxicity. The improved therapeutic window enabled substantially increased tumor clearance by mouse T cell and human chimeric antigen receptor (CAR)-T cell therapy in vivo.

Enhancing T cell therapy through TCR-signaling-responsive nanoparticle drug delivery

Recent far-reaching advances in synthetic biology have yielded exciting tools for the creation of new materials. Conversely, advances in the fundamental understanding of soft-condensed matter, polymers and biomaterials offer new avenues to extend the reach of synthetic biology. The broad and exciting range of possible applications have substantial implications to address grand challenges in health, biotechnology and sustainability. Despite the potentially transformative impact that lies at the interface of synthetic biology and biomaterials, the two fields have, so far, progressed mostly separately. This Perspective provides a review of recent key advances in these two fields, and a roadmap for collaboration at the interface between the two communities. We highlight the near-term applications of this interface to the development of hierarchically structured biomaterials, from bioinspired building blocks to ‘living’ materials that sense and respond based on the reciprocal interactions between materials and embedded cells. This Perspective reviews the complementary developments in synthetic biology and biomaterials and discusses how convergence of these two fields creates a promising design strategy for the fabrication of tailored living materials for medicine and biotechnology. 

/pdf/the-living-interface-between-synthetic-biology-and-3c0rty0m.pdf

The living interface between synthetic biology and biomaterial design

Intracellular organelles are subsystems within a cell, whose activity and chemical composition reflect the metabolic state of live cells. Alterations in cellular homeostasis occurring in disease, ageing and development are also reflected at the level of organelles. By targeting organelles with pharmacological agents and genetic tools, the aim is to improve disease diagnosis and to restore cell function. In this Review, we discuss biological pathways that can be exploited to target the delivery of exogenous cargo with organelle-level precision. We investigate how these pathways can be leveraged for imaging, diagnosis and therapy at the organelle level, and highlight the potential of nucleic acids as delivery systems to target specific organelles in vivo, including the nucleus, lysosomes, secretory organelles and mitochondria. The programmability, modularity and biocompatibility of nucleic acid-based scaffolds make them well suited to accomplishing next-generation targeting with organelle-level resolution in living organisms. Organelles are compartments inside cells that play important parts in intercellular and intracellular communication, reflecting the metabolic state of the cell. This Review discusses biological pathways that can be exploited to target cargo to specific organelles in vivo, highlighting nucleic acids as suitable delivery vehicles for organelle-level imaging, diagnosis and therapy.

Organelle-level precision with next-generation targeting technologies

MicroRNAs (miRs) play an important role in regulating gene expression. Limited by their instabilities, miR therapeutics require delivery vehicles. Tetrahedral framework nucleic acids (tFNAs) are potentially applicable to drug delivery because they prominently penetrate tissue and are taken up by cells. However, tFNA-based miR delivery strategies have failed to separate the miRs after they enter cells, affecting miR efficiency. In this study, an RNase H-responsive sequence is applied to connect a sticky-end tFNA (stFNA) and miR-2861, which is a model miR, to target the expression of histone deacetylase 5 (HDAC5) in bone marrow mesenchymal stem cells. The resultant bioswitchable nanocomposite (stFNA-miR) enables efficient miR-2861 unloading and deployment after intracellular delivery, thereby inhibiting the expression of HDAC5 and promoting osteogenic differentiation. stFNA-miR also facilitated ideal bone repair via topical injection. In conclusion, a versatile miR delivery strategy is offered for various biomedical applications that necessitate modulation of gene expression.

Bioswitchable Delivery of microRNA by Framework Nucleic Acids: Application to Bone Regeneration

A major challenge facing tumor-antigen targeting therapies such as chimeric antigen receptor (CAR)–T cells is the identification of suitable targets that are specifically and uniformly expressed on heterogeneous solid tumors. By contrast, certain species of bacteria selectively colonize immune-privileged tumor cores and can be engineered as antigen-independent platforms for therapeutic delivery. To bridge these approaches, we developed a platform of probiotic-guided CAR-T cells (ProCARs), in which tumor-colonizing probiotics release synthetic targets that label tumor tissue for CAR-mediated lysis in situ. This system demonstrated CAR-T cell activation and antigen-agnostic cell lysis that was safe and effective in multiple xenograft and syngeneic models of human and mouse cancers. We further engineered multifunctional probiotics that co-release chemokines to enhance CAR-T cell recruitment and therapeutic response. Description Editor’s summary Immunotherapy has proven highly efficacious for certain types of blood cancers, but the lower success rates for solid tumors remain a challenge. Vincent et al. designed probiotics that could home in and colonize solid tumors to improve chimeric antigen receptor (CAR) T cell immunotherapy. The two-step approach involved engineering a nonpathogenic strain of Escherichia coli, which delivered synthetic antigens to the tumor microenvironment and “tagged” the tumor (see the Perspective by Bressler and Wong). They next generated CAR T cells that were programmed to recognize these synthetic antigen tags. When the E. coli probiotic was administered, the CAR T cells could be directed to the solid tumors, where they orchestrated tumor cell killing in experimental models of breast and colon cancer. —Priscilla N. Kelly Engineered probiotics produce synthetic targets to facilitate immunotherapy of solid tumors by CAR T cells.

Probiotic-guided CAR-T cells for solid tumor targeting

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 biomaterial functionalization platform can provide new opportunities for immunotherapies.

/pdf/dna-scaffolds-enable-efficient-and-tunable-functionalization-3danz1r0zv.pdf

DNA scaffolds enable efficient and tunable functionalization of biomaterials for immune cell modulation

Phosphorylation-dependent kinetics of Zap70 activation and dissociation.

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DNA scaffolds enable efficient and tunable functionalization of biomaterials for immune cell modulation

Phosphorylation-dependent kinetics of Zap70 activation and dissociation.