Blood–Brain Barrier Regulation: Evolving From Classic Strategies to Electrochemical Ion and Reactive Oxygen Species Control

The blood-brain barrier (BBB), while indispensable for maintaining central nervous system (CNS) homeostasis, constitutes the principal impediment to effective therapeutic delivery for neurodegenerative disorders, particularly hindering spatially resolved modulation of extracellular ions and reactive oxygen species (ROS) within the neural microenvironment. Contemporary electrochemical methodologies have emerged as a paradigm shift for dynamically reconciling these dual parameters, thereby enabling targeted neuroregulation. Critical review of this field reveals a distinct evolution from passive physiological interventions to active electrochemical engineering approaches. Current research, however, encounters persistent translational barriers including insufficient spatiotemporal resolution in neural interfaces, incomplete mechanistic understanding of ROS-ionic crosstalk, and scalability limitations of nanoscale delivery systems. To transcend these limitations, the synergistic convergence of electrochemical platforms with machine learning (ML)-guided predictive analytics, near-infrared (NIR) phototherapy, and biocompatible nanocarrier-mediated delivery systems constitutes a strategic imperative in next-generation neurotherapeutic development. Such interdisciplinary convergence is not merely incremental but rather a fundamental prerequisite for realizing clinically translatable neural microenvironment modulation.