Immunological reprogramming of pain circuitry

The National Institutes of Health Office of the Director awarded The Regents of the University of California, San Francisco $779,000 on September 4, 2026, under the Trans-NIH Research Support program (CFDA 93.310) to develop engineered T cells as programmable therapeutic delivery vehicles for chronic pain treatment.

The research integrates immunology, neuroscience, and synthetic biology to reprogram regulatory T cells with synthetic receptors designed to home to dorsal root ganglia and detect pain-related signals. Upon sensing molecules selectively upregulated in chronic pain conditions, the cells will release anti-nociceptive peptides and cytokines, including enkephalin and IL-10, enabling spatial and temporal control of analgesic action while reducing systemic side effects and tolerance risk. The modular design permits future customization to other pain states or neural circuit disorders.

Performance occurs in San Francisco, California, with a period of performance extending through August 31, 2031. This is a project grant, a standard assistance type under Trans-NIH Research Support, which covers multiple offices in the NIH Office of the Director offering assistance awards to domestic and foreign organizations, universities, hospitals, and other institutions based on scientific merit and program relevance.

Abstract

Chronic pain affects over 20% of american adults and is a leading cause of disability, lost productivity, and opioid dependence. Despite its societal burden, there are few effective treatments that offer durable relief without systemic side effects or risk of addiction. A key challenge is the lack of therapies that can target pain-driving sensory neurons selectively without affecting other tissues or disrupting normal sensory functions. This project proposes a transformative solution by engineering T cells to act as programmable therapeutic delivery vehicles that can detect pain-related signals and secrete natural, durable analgesic signals directly at sites of neural dysfunction. Building on our recent discovery that regulatory T cells can naturally suppress pain through endogenous opioid release, this cross-cutting work integrates immunology, neuroscience, and synthetic biology to reprogram T cells into site-specific modulators of pain. Using synthetic receptors, T cells will be designed to home to dorsal root ganglia, the sensory relay hubs outside the spinal cord, and sense molecules that are selectively upregulated in chronic pain conditions. Only in the presence of these pain-associated signals will the T cells release anti-nociceptive peptides and cytokines, such as enkephalin and IL-10, both of which are known to suppress pain but are difficult to deliver safely using conventional approaches. This strategy allows for spatial and temporal control of analgesic action, reducing the risk of systemic side effects and tolerance which will be directly assessed. The modular design of this system also enables future customization to other pain states or disorders involving neural circuits. Work from this research will establish a new therapeutic platform that treats pain not as a generalized condition, but as a dynamic circuit-level dysfunction that can be modulated with cell-based precision.