Tandem Dual‐Ratiometric SERS Probe Enables Raman Imaging of Neurological pH Fluctuations in Epilepsy

An imbalance of brain pH is closely associated with biochemical reactions, ion regulation, and electrical activity, serving as a hallmark for various neurological disorders. High-resolution imaging of pH fluctuations in brain disease is crucial for understanding pathological processes. However, current pH probes are inadequate for this purpose due to poor blood-brain barrier (BBB) penetration or insufficient specificity. Herein, we reported a tandem dual-ratiometric surface-enhanced Raman scattering (SERS) probe, RHP@AuS, capable of crossing the BBB to address these challenges. RHP@AuS leveraged dendrimers for the facile one-step synthesis of SERS probes, significantly enhancing signal intensity and reproducibility. RHP@AuS can be sequentially activated by neuroinflammation-associated H₂O₂ and pH, exhibiting highly selective ratiometric responses to pH fluctuations in brain disease. Dynamic SERS imaging revealed that during neuronal epileptic activity, inflammation increased and local pH dropped sharply to around 6.6. Building on these findings, a drug combination with dual neuroinflammation-mitigating and pH-regulating properties was developed, effectively alleviating epilepsy in mouse models. This study opens new avenues for developing imaging probes for the brain and deepens our understanding of the roles of pH in neurological disorders.