Cell-specific targeting refers to the ability to target different cells mainly based on sampling the nano-objects exposed on the surface of cell membranes. This is slightly different from cell-specific expression which refers to the concept of using internal state of the cell to determine if a genetic program should be executed or not, or lineage tracing related things.

Both cell-specific targeting and cell-specific expression can be combined. For example, cell-specific targeting could trigger a cell therapy that delivers a gene therapy and that gene therapy might also check for cell-specificty using internal mRNAs or other indicators before executing another genetic program.

See also morphogenesis where cell surface sampling is also important, for cadherins and notch or integrins etc. One difference is that programmable morphogenesis also uses cell-cell signaling for patterning and decision making, not just surface-surface sampling and recognition.

Synthetic receptors for T cell engineering

Programmable synthetic receptors: the next-generation of cell and gene therapies (2024)

  • How synthetic biology sharpens specificity & control in cell therapies: Zhu et al., Cell Mol Immunol (2024). Nature
  • Survey of programmable/synthetic receptors beyond classical CARs: Teng et al. (2024). Nature
  • SynNotch-CAR two-step circuits for multi-antigen precision (review): Shirzadian et al., Front Immunol (2025). PMC
  • synNotch as a general engineered receptor platform (mechanisms & therapeutic cell types): Piraner et al., Nature (2025). Nature

  • Tissue-sensing synNotch circuits that deliver therapeutic payloads in vivo: Simic et al. (UCSF/Lim Lab preclinical). limlab.ucsf.edu

  • synNotch receptors – modular receptors that turn custom cell–cell contacts into gene programs. PubMed

  • chimeric antigen receptors (CARs), see cell therapy

synNotch (synthetic Notch) is an engineered, modular cell-cell communication pathway that lets researchers program custom "if-then" behaviors in living cells based on cell recognition and activation of an internal response. synNotch is a ligand-gated transcriptional switch that turns cell-cell contact into any desired genetic output.

intracellular sensors

check this ref for a section on synthetic intracellular receptors including:

  • Cal-Light (calcium- and light-gated switch)
  • CHOMP (circuits of hacked orthogonal modular protease)
  • intrabody sensor
  • RASER (rewiring of aberrant signaling to effector release)
  • LOCKR (latching orthogonal cage-key proteins)
  • COMET (composable mammalian elements of transcription)
  • POST (phosphoregulated orthogonal signal transduction)

This is obviously off-topic for cell-cell targeting.

Reviews / Overviews

A number of good reviews cover synthetic receptors generally, or synthetic biology tools for cell-based sensing / cell-cell communication, useful background:

Title Highlights / relevance
Programmable synthetic receptors: the next-generation of cell engineering (Teng et al., 2024) Covers CARs, synNotch, SNIPRs, MESA, etc.; design principles, trade-offs, applications. Nature
The evolution of synthetic receptor systems (Manhas et al., 2022) Surveys diverse receptor systems and their integration. NSF Public Access Repository
Small molecule- and cell contact-inducible systems for controlling expression of arbitrary genetic elements (recent paper, Dev, 2025) Combines small-molecule and cell contact inducible systems; good if you want modular “AND”-type behaviour. The Company of Biologists
Recent advances in synthetic Notch receptors for biomedical applications (Song et al., 2025) Deep dive into synNotch variants, modes of multiplexing, tuning etc. Physiology Journals

more

System / Mechanism Key Features / How it works Examples / References Relation / contrasts with synNotch etc.
SNIPRs (Synthetic Intramembrane Proteolysis Receptors) These are synthetic receptors that use regulated intramembrane proteolysis; often similar to synNotch architecture but different activation mechanics; can be tuned for sensitivity. PubMed Zhu et al., Modular design of synthetic receptors for programmed therapeutic cells (2022) describes SNIPRs in human primary T cells. PubMed; also LCB1-SNIPR detecting live virus (SARS-CoV-2) vs synNotch detecting only expressed ligand in cells. eLife
MESA / “NatE MESA” (Natural Ectodomain MESA) receptors MESA = Modular Extracellular Sensor Architecture. These use natural receptor ectodomains (e.g. cytokine receptor ectodomains) plugged in to synthetic modules; orthogonal transcriptional outputs; can sense soluble factors or cues, sometimes modulated by cell contact or proximity. Nature Conversion of natural cytokine receptors into orthogonal synthetic biosensors (Edelstein et al., 2025) describes NatE MESA. Nature
CARs (Chimeric Antigen Receptors) Detect antigens on cell surfaces (membrane bound) and trigger intracellular signals (e.g. T cell activation). Not always modular for custom transcription beyond T cell effector programs, but widely used. CARs are often discussed in same reviews (e.g. in Teng et al.) alongside synNotch, etc. Nature
“Pandora-/SpyTag type” / modular binding / surface display tools Using peptide-tag / protein pairs (SpyTag/SpyCatcher etc.) to bring about adjacency or force binding; could be used to engineer cell contact sensors, adhesion, etc. There are fewer fully developed synthetic receptor applications yet (compared to Notch etc.). I did not find a definitive published system in the reviewed recent literature that uses SpyTag/SpyCatcher specifically as programmed receptor to drive transcription in response to cell contact, though it is used for modular assembly, adhesion, etc.—could be a frontier.
Chemical / peptide-based membrane anchored sensors E.g. artificial or synthetic receptors built from DNA / peptide etc. One example: Ts-pHLIP-Pr – a membrane-anchored synthetic receptor using DNA and peptides to give cells an artificial signaling pathway. ACS Publications

other brain rot

TODO

  • consider surface-bound antibodies?
  • synNotch receptors for programmable antigen targeting
  • multi-receptor logic gating
  • ADR
  • B cell repetoire (BDR) engineering
  • optogenetic activation of cell-cell surface receptors ?
  • optogenetic control of expression of surface-bound antigen or ligand?
  • orthogonal interleukin systems (e.g., synthetic IL-2 variants)
  • multiplexing with synNotch or SNIPR
  • recombination of individual sensor elements or triggers or something? how to generate a toolkit of reconfigurable elements for many cell-cell targets?

One could imagine fusing SpyTag presented on one cell, SpyCatcher fused to receptor extracellular domain on another, with downstream signal transduction. Need to engineer membrane anchoring, perhaps proteolytic release or dimerization leading to transcription.

what about using conformational change in integrin when under tension to trigger downstream signals? or other cadherins, adherins, integrins etc.

exosome surface display of custom scFv / nanobody, and cells that detect exosomes via uptake or just receptor binding

have surfaces expressing complementary binding tags (e.g. zipper domains, SynCAM‐zipper) to bring cells into proximity.

Chemical or non-protein binding modules (aptamers, DNA, peptides) anchored to cell surfaces or display, as sensors. For example the synthetic membrane anchor Ts-pHLIP-Pr is one piece of this direction. ACS Publications