Enzymatic depolymerization of polyurethanes: discovery, mechanisms, and engineering of hydrolases

Polyurethane (PU) is one of the most challenging synthetic polymers for biological recycling because of its microphase-separated architecture, dense hydrogen-bonding networks, diverse bond chemistries, and limited enzymatic accessibility. In response to the urgent need for sustainable plastic recycling, enzymatic PU depolymerization has emerged as a promising strategy for advancing polymer circularity. This review summarizes recent progress in the discovery, mechanistic understanding, and engineering of PU-degrading enzymes. We first discuss current screening approaches, ranging from traditional culture-based assays and high-throughput screening to omics-based mining and machine-learning-assisted candidate prioritization. PU hydrolases are then classified according to their target segments and cleavage sites, with emphasis on cutinases, lipases, and esterases that hydrolyze polyester soft-segment ester bonds, as well as emerging urethanases that target hard-segment carbamate linkages. Recent engineering strategies, including active-site pocket remodeling, loop engineering, and computational simulation-guided rational design using QM/MM simulations, are also reviewed. Despite rapid advances, the degradation of intact bulk PU remains constrained by substrate heterogeneity, phase separation, crosslinking, and poor accessibility of hydrolysable bonds. Therefore, integrated chemo-enzymatic processes, particularly glycolysis followed by selective urethanase-catalyzed hydrolysis, currently represent one of the most practical near-term routes for recovering PU-derived monomers. Finally, we highlight future opportunities in AI-aided enzyme discovery, process-compatible enzyme engineering, and modular chemo-enzymatic bioprocess design for scalable PU biorecycling.