Amyloid β-peptide oligomer (AβO) is widely acknowledged as the promising biomarker for the diagnosis of Alzheimer's disease (AD). In this work, we designed a three-dimensional (3D) DNA walker nanoprobe for AβO detection and real-time imaging in living cells and in vivo. The presence of AβO triggered the DNAzyme walking strand to cleave the fluorophore (TAMRA)-labeled substrate strand modified on the gold nanoparticle (AuNP) surface and release TAMRA-labeled DNA fragment, resulting in the recovery of fluorescent signal. The entire process was autonomous and continuous, without external fuel strands or protease, and finally produced plenty of TAMRA fluorescence, achieving signal amplification effect. The nanoprobe enabled the quantitative detection of AβO in vitro, and the limit of detection was 22.3 pM. Given the good biocompatibility of 3D DNA walker nanoprobe, we extended this enzyme-free signal amplification method to real-time imaging of AβO. Under the microscope, nanoprobe accurately located and visualized the distribution of AβO in living cells. Moreover, in vivo imaging results showed that our nanoprobe could be used to effectively distinguish the AD mice from the wild-type mice. This nanoprobe with the advantages of great sensitivity, high specificity, and convenience, provides an outstanding prospect for AD's early diagnosis development.

Activities of catalase (CAT) and superoxide dismutase (SOD) of ceria nanoparticles (CeO2 NPs) provide the possibility for their application in nervous system oxidative stress diseases including Alzheimer’s disease (AD). The addition of hot electrons produced by a plasma photothermal effect can expand the photocatalytic activity of CeO2 to the near-infrared region (NIR), significantly improving its redox performance. Therefore, we coated both ends of gold nanorods (Au NRs) with CeO2 NPs, and photocatalysis and photothermal therapy in the NIR are introduced into the treatment of AD. Meanwhile, the spatially separate structure enhances the catalytic performance and photothermal conversion efficiency. In addition, the photothermal effect significantly improves the permeability of the blood–brain barrier (BBB) and overcomes the shortcomings of traditional anti-AD drugs. To further improve the therapeutic efficiency, Aβ-targeted inhibitory peptides were modified on the middle surface of gold nanorods to synthesize KLVFF@Au–CeO2 (K-CAC) nanocomposites. We have verified their biocompatibility and therapeutic effectiveness at multiple levels in vitro and in vivo, which have a profound impact on the research and clinical transformation of nanotechnology in AD therapy.

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Redox imbalance and abnormal amyloid protein (Aβ) buildup are key factors in the etiology of Alzheimer's disease (AD). As an antioxidant, the hydrogen molecule (H 2 ) has the potential to cure AD by specifically scavenging highly harmful reactive oxygen species (ROS) such as • OH. However, due to the low solubility of H 2 (1.6 ppm), the traditional H 2 administration pathway cannot easily achieve long-term and effective accumulation of H 2 in the foci. Therefore, how to achieve the continuous release of H 2 in situ is the key to improve the therapeutic effect on AD. As a corollary, we designed a rare earth ion doped g-C 3 N 4 upconversion photocatalyst, which can respond to NIR and realize the continuous production of H 2 by photocatalytic decomposition of H 2 O in biological tissue, which avoids the problem of the poor penetration of visible light. The introduction of CoP cocatalyst accelerates the separation and transfer of photogenerated electrons in g-C 3 N 4 , thus improving the photocatalytic activity of hydrogen evolution reaction. The morphology of the composite photocatalyst was shown by transmission electron microscopy, and the crystal structure was studied by X-ray diffractometry and Raman analysis. In addition, the ability of g-C 3 N 4 to chelate metal ions and the photothermal properties of CoP can inhibit Aβ and reduce the deposition of Aβ in the brain. Efficient in situ hydrogen production therapy combined with multitarget synergism solves the problem of a poor therapeutic effect of a single target. In vivo studies have shown that UCNP@CoP@g-C 3 N 4 can reduce Aβ deposition, improve memory impairment, and reduce neuroinflammation in AD mice.

Despite several attempts, incorporating biological detection that supplies necessary biological information into therapeutic nanotheranostics for hypoxic tumor treatments is considered to be in its infancy. It is therefore imperative to consolidate biological detection and desirable phototherapy into a single nanosystem for maximizing theranostic advantages. Herein, we develop a versatile nanoprobe through combined fluorescence resonance energy transfer (FRET) and oxygenaugmenting strategy, namely APT, which enables glycosylation detection, O 2 self-sufficiency, and collaborative phototherapy. Such APT nanoprobes were constructed by depositing platinum onto gold nanobipyramids (Au NBPs), linking FITC fluorophore-labeled AS1411 aptamers for introducing FRET donors, and by conjugating G-quadruplex intercalated with TMPyP4 to their surfaces via the SH-DNA chain. By installing FRET acceptors on the glycan of targeted EpCAM glycoprotein using the metabolic glycan labeling and click chemistry, FRET signals appear on the cancerous cell membranes, not normal cells, when donors and acceptors are within an appropriate distance. This actualizes protein-specific glycosylation visualization while revealing glycan-based changes correlated with tumor progression. Interestingly, the deposited platinum scavenges excessive H 2 O 2 as artificial nanoenzymes to transform O 2 that alleviates tumor hypoxia and simultaneously elevates singlet oxygen ( 1 O 2 ) for inducing cancer cell apoptosis. Notably, the significant hyperthermia devastation was elicited via APT nanoprobes with phenomenal photothermal therapy (PTT) efficiency (71.8%) for thermally ablating cancer cells, resulting in synergistically enhanced photodynamic−hyperthermia therapy. Consequently, APT nanoprobes nearly actualized thorough tumor ablation while demonstrating highly curative biosafety. This work offers a new paradigm to rationally explore a combined FRET and oxygen-augmenting strategy with a focus on nanotheranostics for hypoxic tumor elimination.