Surface-Cross-linked Protein-like Single-Chain Nanoparticle Globules Unexpectedly Stabilized with a Low Cross-linking Degree

Single-chain nanoparticles (SCNPs) are an emerging new nanomaterial with promising potential for exhibiting compactly collapsed globular nanostructures and associated functions, like proteins. However, the state-of-the-art synthesis approaches often result in SCNPs with diverse morphologies and loosely packed characteristics, even with an ample presence of cross-linkers, resembling sparse structures found in intrinsically disordered proteins. Herein, we present a facile strategy to fabricate protein-like compact SCNP globules using a low content of solvophilic photoreactive agents in a single-component poor solvent via flow photochemistry. Photoreactive agents in our system serve a dual purpose: acting as stabilizing agents that decorate the surface of the precollapsed precursor globules in the poor solvent and cross-linking with neighboring segments in situ upon UV irradiation on the globule surfaces. These cross-linked globules become effectively locked and remain stable when transferred into a good solvent. Computer simulations demonstrate that surface cross-linking reactions primarily occur between cross-linkers and neighboring monomers positioned at long contour distances along the chain backbone. This mechanism locks up the precollapsed protein-like SCNP globules with high efficiency; an extremely low cross-linker content of 1.6 mol % can result in an obvious reduction in molecular size. Small-angle X-ray scattering (SAXS) measurements also confirm the formation of compactly collapsed globule structures. Moreover, by varying the UV irradiation time, the degree of collapse in the SCNPs can be precisely controlled. The residual cross-linkers on the surface render the formed SCNPs reactive, thus allowing for further polymerization into hierarchical multifunctional self-assembly structures.