The Coming of Age of Theranostic Cells

Broadly speaking, theranostics is not just a combination of imaging and therapy [1] but also sensing or sensing/imaging and therapy. The growth trajectory for the theranostics market (including radiotheranostics and nanotheranostics) is estimated to rise from approximately USD 2.5 billion today to USD 8.5 billion by the end of this decade. This growth is propelled by the increasing developments in biomarker discovery and personalised medicine, imaging analytics, wearable devices and digital health tools, and the integration of artificial intelligence in theranostic genome (a blueprint for identifying and optimising the development of theranostic agents) and in enhancing disease diagnosis [1,2,3,4,5]. Other contributing factors include increasing costs of drug discovery, the prevalence of chronic inflammatory diseases, growing cancer patient population, and treatment resistance to conventional cancer chemotherapy and radiation treatments. Today, antibody, nanobody, peptide, and aptamer conjugates (radionuclide and therapeutic agents) are among the key theranostic market drivers aiding the treatment of cancer (e.g., prostate cancer, pancreatic cancer, lymphoma, bone metastases, and neuroendocrine tumours) as well as cardiovascular diseases (e.g., identification and treatment of atherosclerotic plaques) and infectious diseases.

While theranostic/radiotheranostic bioconjugates are performing strongly, theranostic cells (cells designed to both sense and treat disease) are currently coming of age. For example, chimeric antigen receptor (CAR) T cell, often classified under ‘advanced therapies’, is a ‘theranostic cell’. CAR T cells are engineered with sensors and signalling machinery that detect tumour antigens and kills cancer cells [6,7]. Today, Kymriah, Yescarta, Tecartus, and Breyanzi are CAR T cell therapies approved for treating different types of blood cancers. Other CAR T cell developments in the pipeline include senolytic CAR T cells that sense and combat senescence-associated diseases and age-related metabolic dysfunction [8]. There are also advancements with CAR T_reg (regulatory T cells) for treating autoimmune diseases (e.g., ulcerative colitis) and improving the outcome of organ transplantation [9]. CARs are also being incorporated into other immune cell types such as macrophages and natural killer cells with promising anti-tumour responses [9], but theranostic cell engineering is not limited to immune cells. One example is cytokine converter HEK293 cells, which sense pro-inflammatory cytokines associated with psoriasis (i.e., interleukin 22 and tumour necrosis factor) and respond by producing two therapeutic anti-inflammatory cytokines (interleukins 4 and 10) [10]. Other promising efforts include engineered mesenchymal stem cells (MSCs) with transcriptional factors capable of inducing robust angiogenesis for regenerative purposes (e.g., for better prognosis in myocardial infarction) [11] or to produce and secrete extracellular vesicles, including exosomes, to deliver therapeutic cargos and reporter molecules (e.g., fluorescent-based systems, antibody-based biosensors) [12,13]. Other cell sources include bone marrow-derived MSCs, synovial cells, and umbilical cord tissue-derived cells. Moreover, strategies gaining interest for more targeted personalised medicine approaches include the use of engineered cells to produce specific nanobodies or antibody fragments to target cancer cells or their use when labelled with PET or SPECT radioisotopes in theranostics. Despite these developments, depending on cell type, major obstacles still surround safe and efficacious theranostic cell therapies in humans, particularly arising from off-target accumulation, neurotoxicity, and cytokine release syndrome [6,9]. Thus, technological developments that allow for cell tracking and following their spatiotemporal activities and biodistribution with high sensitivity and quantification could pave the way to improving target specificity, overcoming on- and off-target toxicity, and achieving dose optimisation. Direct cell labelling with PET-sensitive radionuclides is a clinically viable approach pertinent to careful dosimetry to prevent radiation damage, particularly with engineered T cells. On the other hand, microfluidic systems for CAR T cell labelling with iron oxide nanoparticles by mechanoporation have been developed and proved successful in cell tracking of solid tumours in animals by magnetic resonance imaging [14]. For local and compartmental applications, one could explore hydrogels and decellularized tissues to sustain engineered cells for prolonged periods to minimise/overcome adverse effects.

Theranostic cell approaches also expand to microbial systems with many potential ex vivo and in vivo applications. Engineering a particular genetic circuit, which responds to specific inputs (as in signals or environmental changes) and produces measurable outputs (as in reporter protein production or colour changes), is often used for generating theranostic bacterial systems [7]. Examples include bacterial cells engineered with an analyte- or a nutrient-responsive promoter that controls the production of a reporter substance (e.g., a fluorescent protein). For protection and overcoming dilution effects in biological fluids such as serum and urine, the incorporation of sensing/diagnosing microorganisms in compatible hydrogel networks is necessary. As for in vivo applications, current developments surround bacterial theranostics that senses and reports on internal inflammatory markers in real time. For example, mice fed with a commensal murine strain of Escherichia coli engineered with a tetrathionate-responsive transcriptional element that produces the reporter β-galactosidase has enabled the diagnosis of gut inflammation in stool samples [15]. Other interesting developments include theranostic microorganisms that modulate the gut microbiome for improved treatment of metabolic diseases and dysbiosis [7] and integrated nanotechnology–biotechnology approaches [16]. An example of the latter is the combination of ingestible environmentally resilient biosensor bacteria and miniaturised luminescence readout electronics that wirelessly communicate with an external device and report on gastrointestinal function and regulation [16].

Taken together, current developments with both mammalian and microbial cell theranostics are creating a new paradigm not only for better understanding of disease mechanisms in real time, but also for drug discovery and for more sensitive sensing/diagnosis of diseases and effective therapeutic interventions, which may be combined with other therapies to further enhance treatment outcomes. Pertinent to realising clinical goals are the further refinement and development of synthetic biology and nanotechnology methods/tools for improved cell engineering and real-time monitoring of their performance in the body. In particular, genetic and bioengineering manipulations of microorganisms for theranostic applications must satisfy and ensure safety, for instance, by removing virulent genes, introducing ‘suicide genes’ if necessary, and apply strategies that maintain genetic stability. Notwithstanding, there are other challenges such as high costs, clinical validation, regulatory hurdles, and availability and investment in healthcare infrastructure, which must be overcome and will impact the growth and maturity of theranostic cell applications in clinical medicine.