Tailoring polymer architectures to drive molecular sieving in protein-polymer hybrids

Protein-polymer hybrids (PPHs) exemplify a transformative intersection of biotechnology and materials science, offering innovative solutions to complex biomedical and engineering challenges. These hybrids synergistically combine the functional specificity of proteins with the structural adaptability of synthetic polymers, resulting in materials with enhanced stability, bioactivity, and responsiveness to environmental stimuli. Advances in reversible deactivation radical polymerization techniques, including atom transfer radical polymerization and reversible addition-fragmentation chain transfer polymerization, have enabled precise control over polymer architecture, molecular weight, and functionality. This precision has facilitated the creation of sophisticated polymer architectures such as block copolymers and complex polymer architectures, tailored for applications including molecular sieving and selective separation. Molecular sieving in PPHs, governed by polymer morphology and protein interactions, holds potential for applications ranging from size-selective separations and enzymatic pathway activation to next-generation therapeutic delivery systems. However, critical challenges remain, including preserving protein activity during synthesis, achieving biocompatibility under physiological conditions, and ensuring long-term stability against proteolytic degradation and pH fluctuations. This review discusses recent advancements in PPHs design, emphasizing synthetic methodologies, advanced characterization techniques, and predictive modeling approaches for achieving varying polymer topologies. It highlights the pivotal role of computational tools, including molecular dynamics simulations and machine learning algorithms, in guiding the design and optimization of these hybrids. Future research should prioritize interdisciplinary approaches to expand protein-polymer interaction datasets, refine predictive models, and enable high-throughput synthesis. Addressing these challenges will accelerate the development of next-generation PPHs for transformative applications in drug delivery, biocatalysis, and molecular separation technologies. • Synergistic protein-polymer hybrids enhance stability, bioactivity, and responsiveness. • ATRP and RAFT enable precise control of polymer architecture and functionality. • PPHs offer molecular sieving for separations, enzymatic pathways, and therapeutics. • Computational tools guide PPHs design using simulations and machine learning models. • Interdisciplinary research drives next-gen PPHs for drug delivery and biocatalysis.