The disruption of Aβ homeostasis, which results in the accumulation of neurotoxic amyloids, is the fundamental cause of Alzheimer's disease (AD). Molecular chaperones play a critical role in controlling undesired protein misfolding and maintaining intricate proteostasis in vivo. Inspired by a natural molecular chaperone, an artificial chaperone consisting of mixed-shell polymeric micelles (MSPMs) has been devised with tunable surface properties, serving as a suppressor of AD. Taking advantage of biocompatibility, selectivity toward aberrant proteins, and long blood circulation, these MSPM-based chaperones can maintain Aβ homeostasis by a combination of inhibiting Aβ fibrillation and facilitating Aβ aggregate clearance and simultaneously reducing Aβ-mediated neurotoxicity. The balance of hydrophilic/hydrophobic moieties on the surface of MSPMs is important for their enhanced therapeutic effect.

The folding process of a protein is inherently error-prone, owing to the large number of possible conformations that a protein chain can adopt. Partially folded or misfolded proteins typically expose hydrophobic surfaces and tend to form dysfunctional protein aggregates. Therefore, materials that can stabilize unfolded proteins and then efficiently assist them refolding to its bioactive form are of significant interest. Inspired by natural chaperonins, we have synthesized a series of polymeric nanochaperones that can facilitate the refolding of denatured proteins with a high recovery efficiency (up to 97%). Such nanochaperones possess phase-separated structure with hydrophobic microdomains on the surface. This structure allows nanochaperones to stabilize denatured proteins by binding them to the hydrophobic microdomains. We have also investigated the mechanism by which nanochaperones assist the protein refolding and established the design principles of nanochaperones in order to achieve effective recovery of a certain protein from their denatured forms. With a carefully designed composition of the microdomains according to the surface properties of the client proteins, the binding affinity between the hydrophobic microdomain and the denatured protein molecules can be tuned precisely, which enables the self-sorting of the polypeptides and the refolding of the proteins into their bioactive states. This work provides a feasible and effective strategy to recover inclusion bodies to their bioactive forms, which has potential to reduce the cost of the manufacture of recombinant proteins significantly.

The disruption of Ab homeostasis, which results in the accumulation of neurotoxic amyloids, is the fundamental cause of Alzheimers disease (AD). Molecular chaperones play a critical role in controlling undesired protein misfolding and maintaining intricate proteostasis in vivo. Inspired by a natural molecular chaperone, an artificial chaperone consisting of mixed-shell polymeric micelles (MSPMs) has been devised with tunable surface properties, serving as a suppressor of AD. Taking advantage of biocompatibility, selectivity toward aberrant proteins, and long blood circulation, these MSPM-based chaperones can maintain Ab homeostasis by a combination of inhibiting Ab fibrillation and facilitating Ab aggregate clearance and simultaneously reducing Ab-mediated neurotoxicity. The balance of hydrophilic/hydrophobic moieties on the surface of MSPMs is important for their enhanced therapeutic effect.

Hybrid particulate composites consisting of noble metal nanoparticles (NPs) and polymeric particles have attracted intensive interest, due to the possibility of combining the precious optical and catalytic properties of the former with the stimuli responsiveness and biocompatibility of the latter. However, it is challenging to prepare hybrid particles that simultaneously have tunable optical and catalytic properties as well as excellent colloidal stability. In the current work, we report a strategy for such hybrid particles, through covalently decorating the outmost surface of mixed shell polymeric micelles (MSPMs) with gold NPs. For this, two block polymers, poly(3-caprolactone)-block-(ethylene glycol) (PCL-b-PEG) and poly(3caprolactone)-block-poly(N-isopropylacrylamide) (PCL-b-PNIPAM), were prepared by ring-opening polymerization and reversible addition fragmentation chain transfer (RAFT) polymerization, respectively. Co-self-assembly of the two block polymers result in MSPMs with a PCL core and a mixed shell consisting of PEG and PNIPAM. At the end of each PNIPAM chain in the shell, thiol groups are introduced to act as anchors for the in situ formation of gold NPs. The number density of the gold NPs is conveniently tuned through varying the relative amount of PEG/PNIPAM in the micellar shell. Reversible shrinking and extension of the PNIPAM chains regulated by temperature can be used to tune the interparticle distance of the gold NPs, while the whole hybrid particles are stabilized by the stretched PEG chains. The hybrid polymeric micelles exhibit thermoresponsive surface plasmon resonance and enhanced catalytic properties as well as excellent colloidal stability. † Electronic supplementary information (ESI) available: XPS, TEM images of gold NP decorated polymeric micelles of PNIPAM or MSPMs of a PEG/PNIPAM mass ratio 1 : 9 aer heating, UV-vis absorption spectra during the reduction of 4-NP catalyzed by pure gold NPs or MSPM@AuNPs aer heating, See