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Design of amyloid β-protein (Aβ) inhibitors is considered an effective strategy for the prevention and treatment of Alzheimer's disease (AD). However, the limited blood–brain barrier (BBB) penetration and poor Aβ-targeting capability restricts the therapeutic efficiency of candidate drugs. Herein, we have proposed to engineer transthyretin (TTR) by fusion of the Aβ-targeting peptide KLVFF and cell-penetrating peptide Penetratin to TTR, and derived a fusion protein, KLVFF-TTR-Penetratin (KTP). Moreover, to introduce the scavenging activity for reactive oxygen species (ROS), a nanocomposite of KTP and manganese dioxide nanoclusters (KTP@MnO2) was fabricated by biomineralization. Results revealed that KTP@MnO2 demonstrated significantly enhanced inhibition on Aβ aggregation as compared to TTR. The inhibitory effect was increased from 18%, 33%, and 49% (10, 25, and 50 μg/mL TTR, respectively) to 52%, 81%, and 100% (10, 25, and 50 μg/mL KTP@MnO2). In addition, KTP@MnO2 could penetrate the BBB and target amyloid plaques. Moreover, multiple ROS, including hydroxyl radicals, superoxide radicals, hydrogen peroxide, and Aβ-induced-ROS, which cannot be scavenged by TTR, were scavenged by KTP@MnO2, thus resulting in the mitigation of cellular oxidative damages. More importantly, cell culture and in vivo experiments with AD nematodes indicated that KTP@MnO2 at 50 μg/mL increased the viability of Aβ-treated cells from 66% to more than 95%, and completely cleared amyloid plaques in AD nematodes and extended their lifespan by 7 d. Overall, despite critical aspects such as the stability, metabolic distribution, long-term biotoxicity, and immunogenicity of the nanocomposites in mammalian models remaining to be investigated, this work has demonstrated the multifunctionality of KTP@MnO2 for targeting Aβ in vivo, and provided new insights into the design of multifunctional nanocomposites of protein–metal clusters against AD. [ABSTRACT FROM AUTHOR]

Metal-organic frameworks (MOFs) are supramolecular nanomaterials, in which metal ions or clusters are connected by organic ligands to form crystalline lattices with highly ordered periodic porous network structure. MOFs have been widely applied in various fields, such as catalyst, sample preparation, and sensing. In recent years, MOFs based surface enhanced Raman scattering (SERS) substrates have attracted much attention since MOFs can largely improve the performance of metallic SERS substrates toward target enrichment and signal enhancement. MOFs have been exploited in SERS analysis to tackle some challenges that bare metal substrates cannot achieve. Combination of MOFs and SERS improved the sensitivity of traditional SERS analysis and extended the application scope of SERS. With the increasing exploration of MOFs based SERS substrates, there is a great demand to review the advances in these researches. Herein, this review concentrated on summarizing the preparation and applications of MOFs based SERS substrates. Representative researches were discussed to better understand the property of MOFs based SERS substrates. The advantages of MOFs based SERS substrates were highlighted, as well as their limitations. In addition, the challenges, opportunities, and future trends in MOFs based SERS analysis were tentatively discussed. [ABSTRACT FROM AUTHOR]