Alzheimer’s disease (AD) is a multifaceted neurodegenerative disorder marked by gradual deterioration in cognitive abilities and alterations in personality and behavior [1]. So far, the exact pathogeny of AD is not fully clear, which leads to no radical treatment. Pharmacological and non-pharmacological treatments can be used to relieve symptoms and interfere with the progression of the disease [2]. However, the existing treatment methods are usually limited to a single pathological factor and fail to achieve the ideal clinical treatment effect [3]. It has been documented that numerous significant pathogenic mechanisms contribute to AD, encompassing amyloid aggregation, oxidative stress, and disruption of metal ion homeostasis [4], [5], [6]. In particular, atypical metabolism of amyloid precursor protein (APP) leads to abnormal aggregation of amyloid-β (Aβ) in the extracellular space of neuronal cells to form toxic aggregates [7]. Aβ aggregates further trigger a series of pathological events, such as oxidative stress and neuroinflammation. When redox metal ion levels are disturbed, especially copper ions (Cu2+), they interact with Aβ peptides to promote aggregation, leading to overproduction of reactive oxygen species (ROS) [8], which in turn exacerbates Aβ deposition [9]. High levels of Cu2+ in amyloid plaque deposits in the brains of AD patients have also been confirmed [10]. Given the interconnectedness of these pathologic factors, the development of drugs with multifunctionality holds great promise. By intervening in multiple pathological pathways simultaneously, to more comprehensive anti-AD. Currently, Aβ therapy is considered as a promising strategy, which aims to alleviate the process of Aβ accumulation and deposition, thereby reducing neuronal damage [11]. The two most prominent variants of the Aβ peptide are Aβ40 and Aβ42, of which Aβ42 is more susceptible to fibrillation and triggers cytotoxicity [12]. Therefore, Aβ42 was taken as the focus of this study. In order to achieve a “multi-pronged attack”, in addition to regulating Aβ aggregation, we also plan to chelate excess Cu2+ and reduce ROS levels in the brain. This comprehensive therapeutic approach is expected to make up for the shortcomings of existing treatments and produce a synergistic effect, thereby delaying the progression of AD.

In the field of AD treatment, researchers are trying to improve the delivery efficiency of drugs to the brain to obtain better therapeutic effects [13]. Several studies have shown that photothermal therapy (PTT) can enhance the permeability of the blood-brain barrier (BBB), thereby improving the efficiency of drug delivery [14]. In this study, a laser of 808 nm, a wavelength characterized by good tissue penetration, was used and applied in the therapeutic strategy of AD [15]. In addition, since Aβ in the patient’s brain has low thermal stability, photothermolysis can be used to absorb light energy and convert it into heat, increasing the local temperature to remove the formed Aβ fibers and mitigate the neurotoxicity it causes [16]. A key advantage of this approach lies in its ability to precisely target and remove these harmful protein deposits without causing damage to surrounding healthy tissues [17]. In recent years, the research field has witnessed the continuous development of photothermal agents, including two-dimensional transition metal-carbon/nitrides [18], magnetic nanoparticles [19], gold nanomaterials [20], and others. Carbon quantum dots (CQD) are ideal for photothermal applications due to their high photothermal conversion efficiency and thermal stability [21], [22]. Under the excitation of a near-infrared (NIR) laser, CQD decomposes Aβ polymers with the help of thermal effects. Notably, the properties of CQD were further tailored by doping with nitrogen, endowing them with the ability to chelate Cu2+. This helps to inhibit the aggregation of Aβ peptides and reduce the fatal damage to neurons. Therefore, the combination of CQD with PTT is expected to mitigate the negative effects of the disease pathology and may become a central component of next-generation AD therapeutic strategies.

The combination of antioxidants and nanomaterials with photothermal properties to enhance efficacy is a new idea for the treatment of AD. Nanoenzymes are widely used in the fields of medicine and environmental protection due to their green, low-cost, and highly stable characteristics [23]. It has been reported that cerium oxide nanoparticles (CeO2), in which the +3 and +4 valence states of cerium can interconvert with each other as well as the presence of oxygen vacancies, exhibit excellent multiple enzyme-like activities, such as superoxide dismutase (SOD) and catalase (CAT) activities [24], [25], [26]. These properties have enabled it to exhibit excellent efficacy in eliminating ROS and thereby reducing apoptosis. It is worth mentioning that the catalytic activity of nanoenzymes is closely related to their size. CeO2 smaller than 5 nm possesses more active sites and thus stronger enzymatic activity due to its larger specific surface area [27]. Therefore, designing small-sized CeO2 as a ROS scavenger is preferred.

Although nanotherapeutics have made great progress, there are still some key problems, such as poor biological stability, limited blood circulation time, and inevitable immune response, which limit their application in vivo [28]. In order to compensate for these shortcomings, the method of using natural cell membrane camouflage has been widely studied and applied [29]. In this context, macrophage membrane (RAW) is particularly prominent due to its natural targeting property [30]. By encapsulating nanoparticles in the RAW, drugs can be delivered to the inflammatory areas in the brain of AD patients, thereby reducing the damage to normal cells and tissues and improving the therapeutic effect. Inspired by this, we first designed a multifunctional biomimetic nanocomposite using RAW as a template, and in-situ grown cerium oxide nanocrystals on it, and then coated on the CQD surface (Scheme 1). This synthesis method has a dual advantage. On the one hand, CeO2 crystallized in situ on the membrane using the one-pot method has an ultra-small size, which optimizes the catalytic activity. On the other hand, the covered RAW confers source cell-related functions such as long cycling, immune evasion, and inflammation targeting of the system while improving the stability of the CQD. Taken together, under NIR irradiation, CQD-Ce-RAW can act as a photothermal agent, a metal ion chelator, and an antioxidant, realizing the goal of multi-pathway therapy and providing a potential solution for the development of more efficient AD treatments.