Topology‐Directed Biomimetic Confinement in Covalent Organic Frameworks Couples Electrocatalytic Water Activation to Reactive Oxygen Species Evolution for Dual‐Potential Electrochemiluminescence

Enzymatic confined microenvironments cooperatively modulate reactive oxygen species (ROS) dynamics to enhance biocatalytic efficiency. Drawing inspiration from this natural mechanism, we developed covalent organic frameworks (COFs) with programmable nanoscale confinement, achieved via topology‐directed assembly. This design enables precise spatiotemporal regulation of ROS generation and scavenging, thereby facilitating highly efficient and unprecedented dual‐potential electrochemiluminescence (ECL). The resulting confined COF architecture exhibits enhanced electronic coupling, attributable to dense π‐stacking, and a well‐ordered, continuous hydrogen‐bonding network templated by functionalized pore walls. By mimicking enzymatic proton‐coupled electron transfer (PCET), the confined environment not only promotes site‐specific ROS generation from electrocatalytic water oxidation but also directs ROS‐mediated redox consumption pathways toward selective population of emissive excited states. As a result, we report the first dual‐potential ECL emission in a COF‐based system, achieving cathodic and anodic ECL efficiencies of 40.5% and 21.2%, respectively, representing 11.3‐ and 8.2‐fold enhancements relative to analogous unconfined COFs. Moreover, size‐selective binding of UO 2 2+ within the confined pores provides direct experimental evidence for confinement‐enabled ROS regulation, yielding quantitative, analyte‐responsive ECL signals. Collectively, these findings establish a broadly applicable principle of confinement‐directed reactivity, grounded in mechanistic understanding and offering a rational, structure‐function‐guided strategy for the design of advanced functional materials.