UW Researchers Build Proteins That Think Before They Act

Researchers at the University of Washington have designed proteins that can decide where and when to act in the body, advancing the goal of highly targeted drug delivery. Such therapies could deliver treatments only to diseased tissues, minimizing side effects elsewhere. The team’s work, described in Nature Chemical Biology , demonstrates therapeutic proteins that respond autonomously to multiple biological cues by folding into preprogrammed shapes, guiding where they travel or activate once inside the body.

The approach centers on adding “smart” tails to proteins that sense and interpret environmental conditions, such as pH or enzyme presence. These tails act like logic circuits, determining whether to remain inactive or trigger a therapeutic event only under specific combinations of biomarkers. Using synthetic biology techniques, the team showed that these programmable proteins could be efficiently produced in days, compared to months required by older chemical methods.

Senior author Cole DeForest explained that building production-ready systems had been a long-standing challenge. “We’ve now finally figured out how to produce these systems faster, at scale and with dramatically enhanced logical complexity,” he said. The work builds on the lab’s earlier efforts to program biomaterials using Boolean logic, a system of AND and OR rules borrowed from computing. By linking therapeutic cargo to carrier materials through sequences that respond to enzymatic degradation in series or parallel, the team could control when and how drugs were released.

In earlier work, those logic-responsive materials required laborious manual chemistry. Advances in protein engineering now allow researchers to program DNA in host cells to create desired protein structures directly. Co-first author Murial Ross noted that new bonding tools “opened doors for new protein structures that were previously unachievable.” By exploiting these tools, the UW researchers produced tailored proteins that can recognize up to five biomarkers and attach to hydrogels, beads, or cells for precise delivery.

One experiment loaded three custom proteins onto a single carrier, each sensitive to a different environmental profile. “Now it takes us a couple of weeks to go from construct design to product,” said DeForest. Potential applications range from cancer therapy to diagnostics that signal the presence of complex biomarker patterns. The team’s long-term aim is to direct materials to exact cellular locations within the body, refining how and where medicines act.