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NIH grant 4DP2EB035891-02: A Novel Class of Synthetic Receptors to Empower the Age of mRNA Therapies
Institute: {'code': 'EB', 'abbreviation': 'NIBIB', 'name': 'National Institute of Biomedical Imaging and Bioengineering', 'admin_org_id': '12500035', 'admin_funding_url': ''}. PI: Xiaojing J Gao. Award: $933114.
Start: 2026-09-19T00:00:00.
Abstract
The COVID vaccination campaigns have highlighted the promise of mRNA-mediated delivery as a novel
therapeutic modality. One particular application is adoptive cell therapy, where immune cells are equipped with
novel functions to treat diseases, e.g., expressing chimeric antigen receptors (CARs) in T cells to ablate cancer
and other undesirable cells. Compared to DNA-based engineering of immune cells, mRNA has several
advantages as a delivery vector, especially its superior safety profile, because it eliminates the risk of randomly
inserting into the host genome and causing mutations, and its short half-life mitigates long-term adverse effects
due to the persistence of the engineered cellular function. Instead of extracting cells from the patient, engineering
them ex vivo, and then reinducing them, researchers have even directly delivered CAR-encoding mRNAs and
created functional CAR T cells in vivo. This is appealing because it has the potential to make adoptive cell
therapy accessible to the general public, its logistics almost as straightforward as manufacturing, distributing,
and administering vaccine shots, in contrast to the costly ex vivo engineering process that will be limited to the
privileged few.
Despite the great potential of mRNA-mediated adoptive cell therapy, there remains a critical need for
tools that enhance targeting precision. It is very rare for a single surface marker, targeted by CAR, to
unambiguously identify one target cell population. Therefore, “on-target/off-caner” killing is a major concern for
CAR T cell therapies against cancer, and the same concern also applies to scenarios of ablating other cells,
such as active fibroblasts in heart infarction or senescent cells. One elegant solution is synthetic receptors, most
notably synthetic Notch, that detect a second marker and express CAR in response, effectively forming AND
logic, where target cells are only killed when both inputs to the synthetic receptor and CAR are present. However,
to our knowledge, all existing synthetic modular, programmable receptors operate at the DNA level, and are
therefore incompatible with mRNA-mediated delivery.
Here we design and demonstrate the feasibility of a first-in-class synthetic modular receptor that operate
at the RNA level. It converts ligand-induced dimerization events into the expression of arbitrary output proteins.
Through extensive computational simulation and experimental optimization, we will expand the input/output
repertoire of this receptor, establish its design principle, enable its encoding on single transcripts and delivery by
mRNA, and take first steps towards improving the precision of ablating active fibroblasts to treat heart infarction.
The impact of such novel receptors is beyond adoptive cell therapy. For example, they can facilitate basic
research by recording cells’ (e.g., neurons) exposure to specific signals (e.g., dopamine). They will benefit a
variety of other biomedical applications too, from expressing antigens or cytokines in response to extracellular
cues to enhance vaccine efficacy, to generating novel sense-and-respond capabilities for tissue engineering.document fetched 2026-09-27 02:45