Adhesive Photoinitiator Constructs Polymer Jackets on Enzymes: Direct, Release-Free Cytosolic Delivery

Enzyme therapeutics require both catalytic activity and efficient cytosolic delivery-yet protective encapsulation typically compromises enzymatic function, while achieving cellular uptake without lysosomal degradation remains challenging. We address this with a rationally designed supramolecular adhesive photoinitiator (^GuCD⊃BP-SH) that unifies surface adhesion, radical initiation, and membrane translocation within a single host-guest architecture. Guanidinium (Gu⁺) motifs on a cyclodextrin scaffold (^GuCD) enable non-covalent adhesion to protein surfaces at carboxylate-rich regions; the cyclodextrin cavity hosts a thiol-benzophenone guest (BP-SH) whose photoactivation (365 nm, 60 mW cm^-2 for 30 min) initiates localized grafting-from polymerization, constructing a semi-permeable polymer jacket. Applied to β-galactosidase, this yields sub-100 nm multi-enzyme nanoassemblies (containing ∼10 enzymes per particle) retaining ∼30% catalytic activity with exceptional proteolytic resistance: 86% activity retained versus 25% for unprotected enzyme after Proteinase K challenge. The incorporated Gu⁺ motifs enable efficient, energy-independent cytosolic delivery via membrane translocation, with 91% of cells showing catalytic activity compared to 5% with non-jacketed enzyme. This modular strategy confers protection and cell-penetrating capability onto native biomacromolecules while maintaining catalytic function, eliminating the need for enzyme release-a persistent bottleneck in therapeutic delivery.