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

## TL;DR

A new method uses a special molecule to coat enzymes with a protective polymer jacket, allowing them to enter cells and work effectively without being destroyed.

## Contribution

A modular strategy using a supramolecular adhesive photoinitiator enables cytosolic delivery of enzymes with retained activity and proteolytic resistance.

## Key findings

- The polymer-jacketed β-galactosidase retains ∼30% catalytic activity and 86% activity after Proteinase K challenge.
- Cytosolic delivery efficiency reaches 91% with the polymer jacket, compared to 5% for non-jacketed enzyme.
- The method preserves enzyme function while enabling direct cytosolic delivery without enzyme release.

## Abstract

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.

A supramolecular adhesive photoinitiator, GuCD⊃BP‐SH, overcomes a central dilemma in enzyme therapeutics. The initiator, featuring a guanidinium‐modified cyclodextrin (GuCD) host, triggers formation of a semi‐permeable polymer jacket directly on an enzyme. This jacket uniquely provides proteolytic resistance and enables direct cytosolic delivery, all while preserving significant catalytic function, thus unifying protection and substrate access.