Researchers at the University of Maryland have identified a promising new way to treat venomous snakebites by borrowing directly from snakes’ own evolutionary defenses. By tapping into toxin-blocking proteins that western diamondback rattlesnakes developed over millions of years to protect themselves, scientists have unlocked a potential blueprint for a powerful, safer, and more universally effective generation of antivenoms.
The innovative approach combines specific proteins found naturally in rattlesnake blood, yielding unusually robust protection against venom from several dangerous snake species. The study was led by Sean B. Carroll, a Distinguished University Professor of Biology at the University of Maryland, and published in the Proceedings of the National Academy of Sciences. The findings offer a fresh pathway toward developing more potent treatments for deadly snakebites, which stubbornly remain a major global health threat, particularly in marginalized and rural regions of the world.
"This is one of those great stories when nature has already solved a problem we’ve been grappling with for decades," said Carroll, who also holds the Andrew and Mary Balo and Nicholas and Susan Simon Endowed Chair at UMD.
The Global Challenge of Snakebites
Despite claiming tens of thousands of lives each year, snakebite envenoming is officially classified by the World Health Organization as one of the world’s most neglected tropical diseases. According to WHO estimates, venomous snakes kill between 80,000 and 140,000 people annually, while hundreds of thousands of survivors are left to cope with permanent physical disabilities, amputations, and psychological trauma.
A significant portion of those affected live in remote, rural areas of developing nations, where acquiring effective antivenom quickly can be a monumental logistical challenge. While existing antivenoms undoubtedly save lives, they are burdened by major clinical and manufacturing drawbacks. Traditional treatments are typically produced by injecting large animals, such as horses or sheep, with low doses of snake venom and then harvesting the resulting antibodies generated by the animals’ immune systems.
Manufacturing these traditional treatments can be extraordinarily costly, and their overall quality and clinical effectiveness can vary widely from batch to batch. Furthermore, traditional antivenoms often fail to neutralize the diverse array of toxins found across different snake species, forcing medical providers to rely on species-specific or regional therapies. They can also trigger severe, sometimes life-threatening immune reactions, such as serum sickness or anaphylaxis, in human patients.
These persistent limitations have driven the global scientific community to urgently search for better, more reliable options. In this latest effort, researchers decided to bypass traditional laboratory assumptions and turn directly to snakes themselves for answers, investigating the physiological traits that allow vipers to survive encounters with their own lethal secretions.
"We’ve known from anecdotes for 100 years that vipers tend to be resistant to their own venom," Carroll explained. "Pero for a long time, nobody knew what exactly was circulating in their blood that protected them."
A Natural Defense Hidden in Rattlesnake Blood
The breakthrough began taking shape in 2022, when Carroll’s laboratory identified a crucial piece of the puzzle: a specific protein known as FETUA-3. The researchers discovered that this naturally occurring protein possessed the remarkable ability to block the activity of numerous metalloproteinase toxins, which are primary components found in western diamondback rattlesnake venom. Additionally, the protein could successfully bind to and inhibit toxins originating from the venoms of several other rattlesnake species.
"Here was evolution’s way for snakes to protect themselves from accidental self-envenomation," Carroll said. That discovery naturally prompted a follow-up question that shifted the research team’s perspective: "Why rely on horse antibodies when nature has packaged an effective antidote right there in the snake?"
To build on this discovery, the research team—including co-author Elda Sánchez, director of the National Natural Toxins Research Center at Texas A&M University-Kingsville—began examining what individual FETUA proteins contribute to overall venom resistance.
The team discovered that individual proteins could counter certain specific effects of venom, but none could do the job alone. One individual protein might successfully reduce internal bleeding, for instance, while another could interfere with specific enzymatic activity. Crucially, however, none of the tested FETUA proteins on its own was able to completely prevent death following a venomous bite.
Protein Combinations Dramatically Boost Protection
The experimental landscape shifted dramatically when the researchers stopped testing the proteins in isolation and instead began combining several FETUA proteins together. These custom mixtures proved to be exponentially more effective at blocking the harmful, systemic effects of venom than any of the individual proteins could achieve on their own.
Pinpointing the ideal combinations is inherently complicated because snake venom is an extraordinarily complex biochemical cocktail. A single sample of snake venom can contain approximately 100 distinct toxin proteins belonging to multiple different protein families, and the exact biochemical composition of venom often differs significantly from one snake species to another.
"The ingredients are there," Carroll said. "We just have to keep testing various mixtures."
In rigorous laboratory experiments, optimized combinations of these natural proteins proved to be roughly 10 times more potent than current sheep-derived rattlesnake antivenoms. Not only did these mixtures completely neutralize the lethal effects of rattlesnake venom, but they also provided broad, cross-species protection against venom from multiple viper species, including species that diverged and separated by millions of years of evolutionary history.
"The fact that parts of these inhibitors have been perfectly conserved over 50 million years of snake evolution tells you just how real a risk this is for these animals," Carroll said. He noted that the exact mechanisms by which snakes envenomate themselves—whether through vulnerable mouth tissue during a strike, by consuming envenomated prey, through cannibalism, or a combination of these factors—remain imperfectly understood by biologists.
Toward a New Generation of Antivenoms
While the current study concentrated heavily on metalloproteinases, which represent one of the most critical and damaging families of venom toxins, the researchers are already applying the exact same broad strategy to target other toxin families.
"We’re getting remarkably close to having effective solutions for the three major toxin families in vipers," Carroll said. "What we’ve learned here, together with research we’re doing now, gives us real confidence that nature-based recombinant antivenoms are within reach."
Looking ahead, Carroll anticipates that the first commercial applications of this "nature’s antivenom" approach will likely emerge in veterinary medicine, treating domestic animals and livestock, with advanced therapies for human snakebites potentially following later down the road.
He envisions a future where next-generation antivenoms protect against a vastly wider range of venoms while remaining inherently safer, less expensive to produce, and much easier to manufacture on a mass scale than many current clinical treatments.
"We could make train cars-worth of this stuff and help solve a massive global health problem," Carroll said. "Many of our most important medicines have come from nature. I’m delighted that the components for a better-than-commercial antivenom were in these snakes all along."
Alongside Carroll, the University of Maryland co-authors included Department of Biology visiting faculty specialists Fiona Ukken and Yetunde Ayinuola. The research was made possible through funding provided by the Howard Hughes Medical Institute and the Viper Resource Center.