Merck & Co. is delving deeper into RNA drug-making, announcing on Tuesday a lucrative deal with biotechnology startup Orna Therapeutics that it hopes could lead to multiple new drugs and vaccines.

Through the deal, Merck will pay Orna $150 million upfront and invest another $100 million in a $221 million Series B round the Cambridge, Mass.-based biotech revealed separately on Tuesday. Orna could receive up to $3.5 billion in downstream payments, as well as royalties on any approved products that come from the deal. The two will work together to develop and commercialize “multiple” programs, including vaccines and therapeutics for infectious diseases and cancer.

The alliance marks Merck’s latest sign of interest in RNA drug-making. The company has dabbled in RNA research over the years but hasn’t yet broken through with an approved product.

In 2006, Merck acquired Sirna Therapeutics, a developer of the type of RNA interference medicines Alnylam Pharmaceuticals is now known for, in a deal worth $1.1 billion. But Merck wrote off the deal eight years later, selling what remained of Sirna’s assets to Alnylam for a fraction of its initial purchase price.

Merck also has longstanding ties with Moderna, the messenger RNA drugmaker that successfully developed a COVID-19 vaccine. Merck first took an equity stake in Moderna in 2015 and has since worked with the company on a few different experimental cancer vaccines. It scrapped an alliance on one of them in February, but still retains partial rights to another in early-stage testing.

Merck has separately invested in other RNA projects, among them the mRNA vaccine maker Translate Bio that Sanofi acquired last year and Skyhawk Therapeutics, a privately held biotech targeting RNA molecules with chemical-based drugs.

Now Merck is turning its attention to a newer RNA drug-making method. Orna is one of a group of companies, among them Laronde and a stealthy startup named Circ Bio, looking to develop medicines from synthetic, “circular” RNA.

This approach is meant to overcome a key limitation of messenger RNA molecules — their short shelf life. Traditional mRNA molecules are linear, unstable and quickly broken down by enzymes in the body, making it challenging to develop therapeutics with staying power. Circular RNAs don’t have the end caps enzymes can grab onto, an advantage proponents claim could lead to more potent therapies with longer-lasting effects. In its statement, Merck cited preclinical data from Orna showing potential “in multiple areas, including vaccines and oncology therapeutics.”

The idea has already drawn sizable investments. Laronde, for example, raised a $440 million round in 2021, and Orna has now secured $321 million in funding since launching last year.

Orna believes its first program, an experimental cancer treatment, will be ready for human testing in 2024.