Polymer–protein
hybrids have been extensively used in biomedical
fields. Polymers with upper critical solution temperature (UCST) behaviors
can form a hydrated coacervate phase below the cloud point (T
cp), providing themselves the opportunity to
directly capture hydrophilic proteins and form hybrids in aqueous
solutions. However, it is always a challenge to obtain a UCST polymer
that could aggregate at a high temperature at a relatively low concentration
and also efficiently bind with proteins. In this work, a UCST polymer
reactive with proteins was designed, and its temperature responsiveness
and protein-capture ability were investigated in detail. The polymer
was synthesized by the reversible addition–fragmentation chain
transfer (RAFT) polymerization of acrylamide (AAm) and N-acryloxysuccinimide (NAS). Interestingly, taking advantage of the
partial hydrolysis of NAS into acrylic acid (AAc), the obtained P(AAm-co-NAS-co-AAc) polymer exhibited an excellent
UCST behavior and possessed good protein-capture ability. It showed
a relatively higher T
cp (81 °C) at
a lower concentration (0.1 wt %) and quickly formed polymer–protein
hybrids with high protein loading and without losing protein bioactivity,
and both the polymer and polymer–protein nanoparticles showed
good cytocompatibility. All the findings are attributed to the unique
structure of the polymer, which provided not only the strong and stable
hydrogen bonds but also the quick and mild reactivity. The work offers
an easy and mild strategy for polymer–protein hybridization
directly in aqueous solutions, which may find applications in biomedical
fields.