A new review in Nature Reviews Bioengineering presents cellular assemblies as a potential new class of “living therapeutics” — biological systems built from organized groups of cells rather than from isolated cells delivered as a suspension. The concept draws on a basic feature of biology: cells rarely operate alone. In tissues, they continuously exchange chemical signals, transmit mechanical forces and adapt their behaviour according to their neighbours. By recreating some of this organization artificially, researchers hope to develop therapies that can sense disease-related conditions, coordinate complex responses and remain active inside the body for longer than conventional cell-based treatments.
The review, led by researchers including Vítor M. Gaspar, João Almeida-Pinto and Bruno S. Moura, examines how cellular assemblies can be designed from the scale of individual cells to larger, hierarchically organized structures. These units may be arranged as linear chains, two-dimensional sheets or three-dimensional aggregates. At each level, the spatial relationship between cells can influence nutrient transport, communication, survival and function. The authors describe this organization as a design space in which the architecture of a therapeutic cell product becomes as important as the identity of the cells themselves.
This distinction matters because free-cell suspensions often encounter severe limitations after administration. Cells injected into damaged tissue or the bloodstream may disperse rapidly, die because of mechanical stress or poor nutrient supply, or fail to remain at the intended site. They may also lack the close cell-to-cell interactions needed to produce coordinated biological effects. In contrast, an assembly can create a local microenvironment in which cells support one another, exchange signalling molecules and respond collectively to external cues. The resulting system may behave less like a population of independent particles and more like a programmable biological tissue.
The review describes how assemblies can sense biochemical signals, including inflammatory mediators, growth factors, metabolites and disease-associated molecules. Cells may also respond to physical information such as stiffness, pressure, fluid flow and geometric confinement. These cues can activate intracellular signalling pathways that alter gene expression, metabolism, migration or the release of therapeutic proteins. When many cells are connected through chemical and mechanical communication, the response can become collective. An assembly might amplify a weak signal, suppress an excessive response or generate a timed sequence of activities, producing behaviour that would be difficult to achieve with dispersed cells.
Building these systems requires both physical and biological engineering tools. Physical approaches can guide cells into defined shapes and arrangements using patterned surfaces, microfluidic devices, 3D printing, bioprinting, acoustic forces, magnetic control or engineered scaffolds. Such methods can determine where cells are located and how closely they interact. Biological approaches can modify the cells themselves through genetic engineering, changes to cell adhesion, synthetic receptors or inducible gene circuits. These circuits can be designed so that cells activate a therapeutic programme only when they encounter a particular molecular signal, potentially improving precision and reducing unwanted activity.
The organization of an assembly also creates gradients and compartments that influence its behaviour. Oxygen and nutrients generally enter from the outside, while waste products move outward, meaning that a large aggregate can contain regions with distinct metabolic states. Rather than being merely a manufacturing challenge, this spatial variation can be used as a functional feature. Different zones within an assembly could contain different cell types or perform separate tasks, such as detecting inflammation, producing a therapeutic mediator and regulating the immune response. However, the same gradients can produce hypoxia, cell death or loss of function if the structure is not carefully engineered.
One of the most important therapeutic advantages discussed in the review is the possibility of achieving more robust tissue repair. In regenerative medicine, organized cell assemblies could provide structural support while releasing signals that attract host cells, stimulate blood-vessel formation or encourage the production of extracellular matrix. The extracellular matrix is the network of proteins and carbohydrates surrounding cells; it supplies physical support and stores biochemical signals that influence cell behaviour. A three-dimensional assembly may therefore act as both a cellular graft and a temporary biological niche, helping damaged tissue rebuild itself rather than simply receiving a bolus of transplanted cells.
Cellular assemblies may also be useful for immunomodulation, where the goal is to control harmful or insufficient immune activity. An engineered assembly could release anti-inflammatory factors in response to signals associated with chronic inflammation, or present molecules that encourage immune tolerance. In cancer and other diseases, assemblies might be designed to concentrate immune-stimulating signals at a target site. Their collective architecture could limit the rapid dilution of secreted factors and allow cells to maintain local communication. At the same time, the review emphasizes that immune interactions are highly context-dependent, and an assembly that is beneficial in one tissue could provoke fibrosis, inflammation or immune rejection in another.
Beyond direct implantation, organized cell systems could serve as biological factories for producing therapeutic mediators. Cells assembled into controlled structures may manufacture proteins, extracellular vesicles, hormones or other active substances more consistently than isolated cells. Their activity could be adjusted through cell composition, geometry, density and genetic programming. Such living production systems may be particularly attractive when a drug has a short half-life or when treatment would benefit from local, sustained release. Yet this promise depends on the ability to control dose, prevent uncontrolled growth and ensure that the cells remain stable over time.
The review identifies translation as one of the field’s central challenges. Manufacturing must be scalable and reproducible, with reliable control over cell number, composition, size, shape, mechanical properties and biological activity. Quality testing will need to go beyond measuring viability. Developers may also need to track spatial organization, communication networks, secretion profiles and changes in function during storage and after implantation. Longitudinal characterization — monitoring the assemblies over extended periods — will be essential because living therapeutics can evolve in response to their environment.
Predictive modelling could help address this complexity. Computational models may connect cellular behaviour to assembly-level properties, allowing researchers to forecast how changes in architecture affect oxygen diffusion, molecular transport, mechanics and therapeutic output. Combining imaging, single-cell analysis, mechanical measurements and mathematical modelling could produce a more complete picture of how assemblies behave inside the body. The authors argue that such tools will be necessary for designing systems with programmable functions rather than relying solely on trial and error.
Cellular assemblies remain an emerging technology, and many questions concerning safety, manufacturing and long-term control are unresolved. Nevertheless, the review presents a compelling shift in perspective: future cell therapies may not be defined only by which cells are administered, but also by how those cells are arranged, connected and instructed to work together. By treating organization as an engineering variable, scientists could develop living therapeutics capable of sensing their surroundings, coordinating a response and adapting over time. The field’s success will depend on turning that biological flexibility into products that are predictable, manufacturable and safe enough for clinical use.
Subject of Research: Cellular assemblies as engineered living therapeutics for regenerative medicine, immunomodulation and biological mediator production.
Article Title: Cellular assemblies as living therapeutics
Article References: Gaspar, V.M., Almeida-Pinto, J., Moura, B.S. et al. “Cellular assemblies as living therapeutics.” Nature Reviews Bioengineering (2026). https://doi.org/10.1038/s44222-026-00470-2
Image Credits: AI Generated
DOI: 10.1038/s44222-026-00470-2
Keywords: cellular assemblies, living therapeutics, tissue regeneration, immunomodulation, cell therapy, tissue engineering, synthetic biology, regenerative medicine, therapeutic cell engineering, biological materials
