By immobilizing enzymes within a polymer cage, chemists at Bielefeld University have created a bulletproof jacket for the biocatalysts, enabling them to operate at record temperatures and efficiencies (Angew. Chem. Novit 2026, DOI: 10.1002/anov.70023). In a proof-of-principle study, a stabilized lipase catalyzed a solvent-free transesterification reaction at 120 °C, permitting high-melting substrates to be used in neat form. The approach could ultimately transform the way industry accesses commodity esters, the team behind the work says.
Biocatalysis is a promising sustainable alternative to conventional chemistry. The technique provides excellent regio- and chemoselectivity, but does not need toxic reagents and harmful solvents. However, the industrial application of enzymes in synthetic processes is typically limited by temperature, solubility, and pH constraints; most reactions require near-physiological conditions to prevent denaturation of the protein-based enzyme. Temperature, in particular, has proved a stumbling block—reaction rates are sluggish at low heat, but many enzymes quickly unravel as temperatures rise above 40 °C.
Harald Gröger and his team hypothesized that introducing spatial constraint within a carefully chosen polymer cage could suppress this problematic unfolding of proteins.
To test their theory, the researchers selected a typical lipase enzyme and combined this with two organic precursors—a hydrazide and an aldehyde—in an aqueous solution. The resulting condensation reaction rapidly constructed a covalent organic framework (COF) around the lipase, and electron microscopy analysis subsequently confirmed that the enzyme was trapped within the pores of this newly formed structure.
Immobilized enzyme in hand, the team then tested the system in a number of control experiments and demonstration reactions. The COF-encapsulated enzyme dramatically outperformed the free enzyme in a deracemization reaction at 100 °C and retained its activity over substantially more reaction cycles compared with a standard surface-supported lipase.
The system also proved extremely efficient when used under solvent-free conditions: vanillyl alcohol and vinyl hexanoate—two waxy substances that melt slightly above 100 °C—formed their expected product (vanillyl hexanoate, a flavor additive) in 99% yield and in just 1 h without the need for added solvent.
“It’s really solid work. They have robust experiments that show the enzyme is not leaching, and the reusability is superhigh at 100 °C. They have an exceptional number of cycles,” says Francesca Paradisi, a biocatalysis researcher at the University of Bern. “It’s really clear it’s a very stable system, likely suitable for industrial applications.”
Industry is certainly where the team’s ambitions lie—notably, the production of cosmetic and commodity esters—and the researchers were therefore keen to demonstrate the feasibility of this approach in both flow and batch reactor systems. The immobilized enzyme formed vanillyl hexanoate in 99% yield in a batch process and, under flow conditions in the team’s example deracemization reaction, the same system achieved 50% conversion—the theoretical maximum for a kinetic resolution.
“On a large scale, I think it would be very promising to embed these materials into a fixed-bed reactor and then have a flow process in which you pump your substrates through this,” Grӧger says. “A key issue is the access to the COF-embedded catalyst on a larger scale, its fine tuning, and the scalability of the bioprocess.”
The approach provides access to a completely new process window that you don’t usually see with enzymes, says Sebastian Cosgrove, a biocatalysis researcher at Keele University. But one big question remains: How generalizable is this strategy? “The benefit you have with these systems is the tunability of the actual framework,” he says. “It would be really interesting to look at encapsulation of different enzymes or multienzyme cascades within the pores of the frameworks themselves and see what else you can do with this.”
