Alzheimer's disease (AD) is a progressive and irreversible brain disorder. Recent studies revealed the pivotal role of β-amyloid (Aβ) in AD. However, there is no conclusive indication that the existing therapeutic strategies exerted any effect on the mitigation of Aβ-induced neurotoxicity and the elimination of Aβ aggregates simultaneously in vivo. Herein, we developed a novel nanocomposite that can eliminate toxic Aβ aggregates and mitigate Aβ-induced neurotoxicity in AD mice. This nanocomposite was designed to be a small-sized particle (14 ± 4 nm) with Aβ-binding peptides (KLVFF) integrated on the surface. The nanocomposite was prepared by wrapping a protein molecule with a cross-linked KLVFF-containing polymer layer synthesized by in situ polymerization. The presence of the nanocomposite remarkably changed the morphology of Aβ aggregates, which led to the formation of Aβ/ nanocomposite coassembled nanoclusters instead of Aβ oligomers. With the reduction of the pathological Aβ oligomers, the nanocomposites attenuated the Aβ-induced neuron damages, regained endocranial microglia's capability to phagocytose Aβ, and eventually protected hippocampal neurons against apoptosis. Thus, we anticipate that the small-sized nanocomposite will potentially offer a feasible strategy in the development of novel AD treatments.

Safe and efficient delivery of blood-brain barrier (BBB)–impermeable cargos into the brain through intravenous injection remains a challenge. Here, we developed a previously unknown class of neurotransmitter–derived lipidoids (NT-lipidoids) as simple and effective carriers for enhanced brain delivery of several BBB-impermeable cargos. Doping the NT-lipidoids into BBB-impermeable lipid nanoparticles (LNPs) gave the LNPs the ability to cross the BBB. Using this brain delivery platform, we successfully delivered amphotericin B (AmB), antisense oligonucleotides (ASOs) against tau, and genome-editing fusion protein (−27)GFP-Cre recombinase into the mouse brain via systemic intravenous administration. We demonstrated that the NT-lipidoid formulation not only facilitates cargo crossing of the BBB, but also delivery of the cargo into neuronal cells for functional gene silencing or gene recombination. This class of brain delivery lipid formulations holds great potential in the treatment of central nervous system diseases or as a tool to study the brain function.

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.

Folding and unfolding are essential ways for a protein to regulate its biological activity. The misfolding of proteins usually reduces or completely compromises their biological functions, which eventually causes a wide range of diseases including neurodegeneration diseases, type II diabetes, and cancers. Therefore, materials that can regulate protein folding and maintain proteostasis are of significant biological and medical importance. In living organisms, molecular chaperones are a family of proteins that maintain proteostasis by interacting with, stabilizing, and repairing various non‐native proteins. In the past few decades, efforts have been made to create artificial systems to mimic the structure and biological functions of nature chaperonins. Herein, recent progress in the design and construction of materials that mimic different kinds of natural molecular chaperones is summarized. The fabrication methods, construction rules, and working mechanisms of these artificial chaperone systems are described. The application of these materials in enhancing the thermal stability of proteins, assisting de novo folding of proteins, and preventing formation of toxic protein aggregates is also highlighted and explored. Finally, the challenges and potential in the field of chaperone‐mimetic materials are discussed.

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Personalized cancer vaccination using nanomaterials holds great potential for cancer immunotherapy. Here, a nanochaperone (PBA‐nChap) is tailored for in situ capture of tumor‐associated antigens (TAAs) to improve cancer immunotherapy. The PBA‐nChap is capable of i) efficiently capturing TAAs in situ; ii) protecting TAAs from degradation; iii) transporting TAAs to antigen‐presenting cells and promoting cross‐presentation. Intratumor injection of PBA‐nChap in combination with pretreatment with photodynamic therapy (PDT) significantly enhances immune response and exhibits excellent antitumor efficacy. Moreover, nanovaccine prepared by simply co‐culturing PBA‐nChap with tumor cell fragments from surgery resected primary tumor in vitro synergized with immune checkpoint blockade (ICB) therapy can effectively inhibit tumor recurrence and metastasis after an operation. This work provides a promising platform for personalized cancer vaccination.

Nanochaperones have been designed and used for regulating the (re)folding of proteins, treating protein misfolding‐related diseases, and, more recently, in drug delivery. Despite various successes, a complete understanding of the working mechanisms remains elusive, which represents a challenge for the realization of their full potential. Here, we thoroughly investigated the functioning of differently charged nanochaperones that regulate the refolding of thermally denatured lysozyme. We found that the balance between the capture and release of lysozyme clients that are controlled by nanochaperones plays a key role in regulating refolding. More importantly, the findings could be applied to other enzymes with various physicochemical properties. On the basis of these results, we could recover the activity of enzymes with high efficiency either after 20 days of storage at 40 °C or heating at high temperatures for 30–60 min. Our results provide important new design strategies for nanochaperone systems to improve their properties and expand their applications.

Protein misassembly leads to the formation of dysfunctional and toxic molecular species relating to neurodegeneration in Parkinson's disease and Alzheimer's disease. Here, we tailored a nanochaperone (αS‐nChap) for α‐synuclein to regulate its assembly. The αS‐nChap is capable of i) specifically recognizing α‐synuclein; ii) dynamically capturing and stabilizing monomeric α‐synuclein and retarding oligomerization; iii) tightly capturing oligomeric α‐synuclein to prevent fibrillization; and iv) transporting α‐synuclein oligomers to the lysosomal degradation system. The regulation of α‐synuclein assembly by αS‐nChap was studied in vitro. Moreover, the role of αS‐nChap preventing α‐synuclein pathology in cells and protecting neurons from apoptosis was investigated. The strategy of tailoring a nanochaperone to regulate aberrant assembly of pathogenic proteins provides important insights into protein misfolding diseases. We foresee that αS‐nChap has therapeutic value for Parkinson's disease.