Alzheimer's disease (AD), a neurodegenerative disorder, currently affects about 50 million people worldwide and causes a huge social and economic burden [1], [2]. The pathogenesis of AD is complex and multifactorial. Studies found that β-amyloid (Aβ) protein aggregation [3], tau hyperphosphorylation [4], cholinergic deficiency [5], inflammation [6], oxidative stress [7], and metal dyshomeostasis [8] were the main common manifestations in AD patients. Over the past three decades, the U.S. Food and Drug Administration (FDA) has approved only ten single-target drugs for AD treatment (Fig. 1​), which can be classified as cholinesterase inhibitor (ChEI), N-methyl-D-aspartic acid receptor (NMDAR) antagonist and Aβ-targeted monoclonal antibody (McAb). However their therapeutic effects remain limited [9]. Therefore, multi-target therapeutic strategies have become one of the popular research directions in the field of AD. Notably, accumulating evidence suggested that almost all the common manifestations of AD could be associated with metal homeostasis. Neurodegeneration might occur due to the association between metals and proteins, which was then followed by aggregate formation, mitochondrial disorder, and, ultimately, cell death [1].

Homeostasis of zinc is closely related to AD and zinc level is a double-edged sword for the treatment of AD. Zinc is an essential trace element, stabilizing protein structures and catalyzing biochemical processes in living organisms. It exhibited antioxidant and anti-inflammatory properties crucial for brain function. Deficiency of zinc, as well as overloaded copper, manganese, or iron activated the signaling pathways of the inflammatory, oxidative and nitrosative stress response [1]..Studies also showed that certain concentrations (around 5–10 μM) of zinc demonstrated protective effects against neurotoxicity caused by Aβ proteins [10]. Epidemiological evidence also suggested that zinc supplementation was associated with reduced risk and slower cognitive decline, in people with AD [11]. However, excessive zinc accumulation in the brain may enhance Aβ adhesion, promoting aggregation and plaque formation [12], [13].

Homeostasis of copper is also important. However, compared with zinc level, population-based studies showed that AD patients exhibited significantly elevated serum copper levels than those in the control group [2]. Copper ions bound with high affinity to Aβ peptide, increasing the proportion of β-sheet structures within the peptide, which led to Aβ aggregation [14]. Copper ions could also complex with Aβ fibrils, producing hydrogen peroxide in the presence of biological reductants [15]. In addition, several clinical studies demonstrated that elevated free copper levels correlated with Aβ and tau protein levels in pathologic cerebrospinal fluid [2].

Metal chelators might disrupt the coordination of Cu2+/Zn2+ to Aβ peptides, thereby inhibiting metal-induced Aβ aggregation and reactive oxygen species (ROS) generation, constituting a promising anti-AD strategy. Representative metal chelators, such as 8-hydroxyquinoline, thioflavin T, and benzothiazole derivatives, might exhibit optimized blood brain barrier permeability and low cytotoxicity, and several analogues have advanced to phase II clinical evaluation, offering disease-modifying potential [16], [17], [18], [19].

Porphyrins have four nitrogen atoms that can chelate with metal ions, which is expected to be used in the regulation of metal homeostasis [20]. Metalloporphyrins can also be considered as potential therapeutic candidates for AD due to their planar structure, hydrophobicity and low toxicity. For example, it was found that metal tetraphenyl porphyrin structure could effectively inhibit the electrostatic interaction of Aβ and efficiently suppress the aggregation of Aβ [21]. Furthermore, as a fluorophore, porphyrin has a large planar conjugated structure, large Stokes shift (>100 nm), long emission wavelength (>650 nm), good chemical stability and other excellent spectral characteristics, and thus could be used as a near infrared fluorescent probe [22], [23].

Therefore, in this work a multi-target anti-AD strategy centered on regulating metal homeostasis was applied (Fig. 2). One novel porphyrin carbamate derivative 1 and its zinc complex 1-Zn were designed and synthesized. 1-Zn might be used to deliver zinc and at the same time competitively chelate over-loaded Cu2+. This dual-action approach leveraged the higher thermodynamic stability of Cu2+-porphyrin complex compared to Zn2+-porphyrin, which is expected to ensure gradual Zn2+ displacement by Cu2+ in Cu2+-rich environments. By simultaneously supplementing Zn2+ and sequestering Cu2+, these porphyrins may mitigate metal dyshomeostasis in AD, offering a targeted therapeutic strategy. Upon administration, 1-Zn could release Zn2+ to restore synaptic Zn2+ pools, inhibit Aβ aggregation, alleviate the cholinergic deficiency and bind Cu2+ via transmetallation, neutralizing its redox activity and reducing oxidative damage. Notably, the single crystals of 1 and 1-Zn were obtained and characterized by X-ray single crystal diffraction, which led to an in-depth study of their structural information. Meanwhile, when Cu2+ was added to the solution of 1 or 1-Zn, a significant fluorescence shut-off response was observed, which made them potential candidate for diagnosis of over-loaded copper ions.