DARPA Funds Genetic Engineering of Blood Cell Precursors to “Enhance” Warfighters

On September 1, 2026, the Defense Advanced Research Projects Agency (DARPA) started Phase 1 of a program to genetically engineer red blood cell precursors so they can temporarily “enhance physiological resilience” and “support warfighter performance in extreme environments.” Under the Smart Red Blood Cells (Smart-RBC) program, researchers are modifying the precursor cells that become red blood cells so the mature cells contain new biological circuits capable of sensing changes in the body, interpreting those signals, and releasing substances that alter metabolism or clotting.

The program aims to improve exercise tolerance and to more quickly control bleeding after injury. This is currently a three-year program with no clinical trials or direct human testing, but it already includes studies on how the technology would be accepted and used.

UC San Diego announced a DARPA contract worth up to $11.3 million to conduct research on the project. A $14 million contract was announced with Scarlet Therapeutics in late September to “coordinate a multidisciplinary, international consortium” in the development of SRBCs.

John Carethers, MD, vice chancellor for Health Sciences at UC San Diego, said “DARPA follows a ‘moonshot’ model, where the goal is nearly impossible but successful projects can be highly impactful, and our researchers tackle those challenges head on in order to push the boundaries of biomedical science.” Other UC San Diego researchers described blood cell engineering as “an emerging field” and said this project “has the potential to revolutionize the field of red blood cell engineering.” The researchers indicate that the technology has future possibilities to be used in cancer treatment, to improve athletic performance, and to prevent heart attacks, stroke, vascular diseases, and diabetic skin ulcers.

DARPA suggests SRBCs are a potential solution that balances safety and speed for modern warfighting. Emergency medical countermeasures, pharmaceuticals, and simulated acclimation are labeled as “fast, but incomplete and risk of side effects,” while natural acclimation and diet, sleep, and exercise are safe, but slow.

The three-year project is split into two 18-month phases. The goal of the first phase is to demonstrate that new proteins can be produced, correctly positioned, and retained inside mature red blood cells. The second phase will build full circuits and test functional prototypes. Precursor cells will be genetically modified using tools like CRISPR/Cas, lentiviral vectors, or AAV, so that the mature, nucleus-free cells still contain the engineered proteins.

Those proteins form a three-layer biological circuit: sensors that detect at least two different biomarkers in the blood, molecular logic gates that interpret the signals, and an output that amplifies the response at least 100-fold so the cell produces an effector molecule capable of changing metabolism or clotting. The final cells must meet quantitative safety metrics for size, shape, circulation time, clotting behavior, inflammation markers, and oxidative stress when tested in the lab or in animal models such as humanized mice or pigs.

There is a dedicated eligibility, adoption, and adherence assessment team that examines barriers to acceptance by warfighters, adherence in military and civilian settings, medical infrastructure needs, and the safety and efficacy implications of repeated transfusions or ongoing activation of the circuits. DARPA intends to work with the Army’s Office of Regulated Activities and the FDA’s Center for Biologics Evaluation and Research to discuss the regulatory pathway for future SRBC products.

DARPA states, “The final mature SRBCs must be enucleated to minimize the risk of transferring modified genetic material to a prospective recipient.” The program description emphasizes, “Safety is paramount; Smart-RBC specifically utilizes enucleated RBCs, which cannot transfer genetic material, mitigating potential risks to recipients.”

This technology is not risk-free, even if the final product is enucleated. The newer gene-editing tools, which are often described as safer than CRISPR, can still damage DNA in the blood-forming stem cells used as the starting material for SRBC. A 2023 study in Nature Biotechnology found that base and prime editors produced DNA breaks, deletions, and chromosomal rearrangements in these cells. They also increased the overall number of random mutations across the genome.

These types of genetic changes in blood stem cells are linked with serious blood disorders, like leukemia and other blood cancers. It is also associated with reduced production of healthy red cells, white cells, and platelets. SRBCs begin with gene-edited precursor cells. Any unintended damage during the manufacturing process would need to be identified so it doesn’t carry over into the final red blood cells or compromise their safety.

According to DARPA’s program overview, the red blood cells circulate for up to 120 days. The agency says engineered RBCs are safe because there is minimal risk associated with genetic engineering since the cells contain no nucleus and there are accurate animal models.

While the initial phases do not include any human testing or clinical tests, the materials do call for the use of humanized mice and humanized pigs for potential in vivo models for testing engineered red blood cells. Many documented welfare risks are associated with experiments involving humanized mice. A 2025 peer-reviewed study in Frontiers in Immunology on humanized mouse models notes that “Graft-versus-Host Disease (GvHD) is a significant complication following xenogeneic transplantation of human immune cells into mice, limiting their lifespan and impacting the utility of these studies.”

Common side effects include weight loss, swelling or reddening of extremities, poor fur condition, and changes in posture. The authors also emphasize the need for refined scoring systems and early interventions to “minimize suffering when working with humanized mice.”