Near-Infrared II ratiometric photoacoustic imaging of copper ions in Alzheimer’s disease mice by using biomineralized nanoprobes

• The ZnS-ICG NPs exhibit absorption in the NIR-II window, facilitating deeper tissue penetration (up to 6 mm) and high spatial resolution (10 µm). • Utilizing a simple cation exchange, our nanoprobes enabling precise ratiometric imaging of Cu 2+ with a sensitivity of 0.22 mM. • The ability of ZnS-ICG NPs to bypass the blood-brain barrier via the meningeal lymphatic pathway marks a significant advancement. • ZnS-ICG NPs demonstrate potential neuroprotective properties by mitigating copper-induced oxidative stress. Copper ion dysregulation is intricately associated with the development of Alzheimer’s disease (AD). Photoacoustic imaging (PA) of copper ions in the first near-infrared window (NIR-I, 650–950 nm) provides a nonradiative and noninvasive imaging technique for diagnosing AD. However, this method has challenges related to limited tissue penetration and high background signal interference. Here, we developed biomineralized indocyanine green-loaded ZnS nanoprobes (ZnS-ICG NPs) for ratiometric PA imaging of copper ions in the second near-infrared window (NIR-II, 1000–1700 nm). These biomineralized NPs utilized a cation exchange mechanism to convert ZnS-ICG to CuS-ICG, which significantly enhanced NIR-II absorbance while preserving ICG absorbance in the NIR-I range, thereby enabling deep and background interference-free NIR-II ratiometric PA imaging of copper ions. Importantly, ZnS-ICG NPs crossed the blood–brain barrier through the meningeal lymphatic system, thereby facilitating efficient brain delivery. These NPs provided high spatial resolution (10 µm), penetrated up to 6 mm into the brain tissue, and detected copper ions with a sensitivity of 0.22 mM in AD mouse models. ZnS-ICG NPs exerted neuroprotective effects by mitigating copper-induced oxidative stress. Thus, this multifunctional platform offers significant insights into copper ion dynamics in AD and has potential for application in targeted diagnostic and therapeutic approaches.