Inspired by the natural motors, artificial nanomotors (NMs) have emerged as intelligent, advanced, and multifunctional nanoplatforms that can perform complex tasks in living environments. However, the functionalization of these fantastic materials is in its infancy, hindering the success of this booming field. Herein, an inhibitor-conjugated nearinfrared (NIR) laser-propelled Janus nanomotor (JNM-I) was constructed and first applied in the modulation of amyloid-β protein (Aβ) aggregation which is highly associated with Alzheimer's disease (AD). Under NIR light illumination, JNM-I exhibited efficient propulsion through the "self-thermophoresis" effect, and the active motion of JNM-I increased the opportunity of the contacts between the immobilized inhibitors and Aβ species, leading to an intensification of JNM-I on modulating the on-pathway Aβ aggregation, as evidenced by the distinct changes of the amyloid morphology, conformation, and cytotoxicity. For example, with a NIR irradiation, 200 μg/mL of JNM-I increased the cultured SH-SY5Y cell viability from 68% to nearly 100%, but it only protected the cells to 89% viability without an NIR irradiation. Meanwhile, the NIR irradiation effectively improved the blood−brain barrier (BBB) penetration of JNM-I. Such a JNM-I has connected artificial nanomotors with protein aggregation and provided new insight into the potential applications of various nanomotors in the prevention and treatment of AD.

The fibrillization and deposition of β‐amyloid protein (Aβ) are recognized to be the pathological hallmarks of Alzheimer's disease (AD), which signify the need for the effective detection and inhibition of Aβ accumulation. Development of multifunctional agents that can inhibit Aβ aggregation, rapidly disaggregate fibrils, and image aggregates is one of the effective strategies to treat and diagnose AD. Herein, the multifunctionality of nitrogen‐doped carbonized polymer dots (CPDs) targeting Aβ aggregation is reported. CPDs inhibit the fibrillization of Aβ monomers and rapidly disintegrate Aβ fibrils by electrostatic interactions, hydrogen‐bonding and hydrophobic interactions with Aβ in a time scale of seconds to minutes. Moreover, the interactions make CPDs label Aβ fibrils and emit enhanced red fluorescence by the binding, so CPDs can be used for in vivo imaging of the amyloids in transgenic Caenorhabditis elegans CL2006 as an AD model. Importantly, CPDs are demonstrated to scavenge the in vivo amyloid plaques and to promote the lifespan extension of CL2006 strain by alleviating the Aβ‐triggered toxicity. Taken together, the multifunctional CPDs show an exciting prospect for further investigations in Aβ‐targeted AD treatment and diagnosis, and this study provides new insight into the development of carbon materials in AD theranostics.

Fibrillogenesis of amyloid β-protein (Aβ) has been thought to be implicated in the progression of Alzheimer's disease (AD). Therefore, development of highefficiency inhibitors is one of the strategies for the prevention and treatment of AD. Serum albumin has been found to capture Aβ monomers through its hydrophobic groove and suppress amyloid formation, but the inhibition efficiency is limited. Inspired by the strong inhibition potency of a basic protein, human lysozyme, we have herein proposed to develop a basified serum albumin by converting carboxyl groups into amino groups with ethylenediamine conjugated on the protein surface. The idea was verified with both bovine and human serum albumins (BSA/HSA). Four basified BSA (BSA-B) preparations with amino modification degrees (MDs) from 8.0 to 41.5 were first synthesized. Extensive biophysical and biological analyses revealed that the inhibition potency significantly increased with increasing amino MD. BSA-B of the highest MD (41.5), BSA-B4, which had an isoelectric point of 9.7, presented strong inhibition on Aβ 42 fibrillation at a concentration as low as 0.5 μM, at which it functioned similarly with 25 μM native BSA to impede 25 μM Aβ fibrillation. Cell viability assays also confirmed that the detoxification of 5 μM BSA-B4 was superior over 25 μM native BSA by increasing cell viability from 60.6% to 96.0%. Fluorescence quenching study unveiled the decrease of the binding affinity between Aβ 42 and the hydrophobic pocket region of BSA-B4, while quartz crystal microbalance experiments demonstrated that the binding constant of BSA-B4 to Aβ 42 increased nearly 5 times. Therefore, the increase of electrostatic interactions between BSA-B4 and Aβ 42 was the main reason for its high potency. Hence, aminated BSA achieved a conversion of binding way to Aβ from a mainly single-site hydrophobic binding to multiregional electrostatic interactions. Similar results were obtained with basified HSA preparations on inhibiting the amyloid formation and cytotoxicity. This work has thus provided new insights into the development of more efficient protein-based inhibitors against Aβ fibrillogenesis.

Theranostics, the combination of therapeutics and diagnostics, has emerged as a sophisticated, integrated, and advanced tool in the prevention and treatment of serious diseases, such as Alzheimer’s disease (AD). However, the preclinical research of an AD theranostic molecule is in its infancy and needs to be explored in depth. Herein, a multifunctional theranostic agent is designed and fabricated by conjugating an Aβ-specific near-infrared (NIR) fluorescence probe (F) and by coupling a BBB penetrable peptide (Penetratin, Pen) onto the basified human serum albumin (HSA-B) that has been recently proven as an effective amyloid-β (Aβ) inhibitor. Such an elaborately constructed HSA-B-based molecule (HSA-BFP) possesses high potency on inhibiting Aβ fibrillogenesis, for example, increasing SH-SY5Y cell viability from 66.5 to 93%. In addition, HSA-BFP exhibits favorable stability in the “off–on” NIR imaging of Aβ plaques and achieves a 2-fold increase of BBB permeability after the Pen modification. More importantly, in vivo assays with the AD model C. elegans CL2006 indicate that HSA-BFP can specifically image Aβ deposits, decrease amyloid accumulation, and attenuate Aβ-triggered paralysis. Thus, HSA-B has been proven as a potent and versatile platform for the development of AD theranostic agents.

Fibrillogenesis of amyloid β-protein (Aβ) is pathologically associated with Alzheimer’s disease (AD), so modulating Aβ aggregation is crucial for AD prevention and treatment. Herein, a zwitterionic polymer with short dimethyl side chains (pID) is synthesized and conjugated with a heptapeptide inhibitor (Ac-LVFFARK-NH2, LK7) to construct zwitterionic polymer–inhibitor conjugates for enhanced inhibition of Aβ aggregation. However, it is unexpectedly found that the LK7@pID conjugates remarkably promote Aβ fibrillization to form more fibrils than the free Aβ system but effectively eliminate Aβ-induced cytotoxicity. Such an unusual behavior of the LK7@pID conjugates is unraveled by extensive mechanistic studies. First, the hydrophobic environment within the assembled micelles of LK7@pID promotes the hydrophobic interaction between Aβ molecules and LK7@pID, which triggers Aβ aggregation at the very beginning, making fibrillization occur at an earlier stage. Second, in the aggregation process, the LK7@pID micelles disassemble by the intensive interactions with Aβ, and LK7@pID participates in the fibrillization by being embedded in the Aβ fibrils, leading to the formation of hybrid and heterogeneous fibrillar aggregates with a different structure than normal Aβ fibrils. This unique Trojan horse-like feature of LK7@pID conjugates has not been observed for any other inhibitors reported previously and may shed light on the design of new modulators against β-amyloid cytotoxicity.