Sulfonated Ionic Covalent Organic Frameworks With Dual‐State Activation for Synergistic Photodynamic‐Ferroptosis Therapy

ABSTRACT Conventional photocatalysis is fundamentally constrained by the competitive nature of excited‐state dynamics, which typically restricts utilization to a single excitonic channel. Consequently, simultaneously harvesting both excitons to maximize reactive oxygen species (ROS) generation remains a formidable challenge in cancer theragnostic. Herein, an ionic engineering strategy is developed to overcome this excitonic bottleneck by constructing sulfonated covalent organic frameworks (BD‐SO ₃ ‐COF) via backbone quaternization. This specific ionic modulation imparts a strong push‐pull electronic landscape that fundamentally reshapes excited‐state dynamics. Mechanistically, the sulfonate moieties suppress the parasitic radiative recombination of singlet excitons (S ₁ ) to boost superoxide anion (O ₂ ^•− ) generation specifically at the electron‐deficient quaternized pyridine rings (redox sites), while simultaneously populating long‐lived triplet excitons (T ₁ ) on the porphyrin macrocycles that activate molecular oxygen via an efficient Dexter energy transfer pathway to produce singlet oxygen ( ¹ O ₂ ). Capitalizing on this site‐specific dual‐state activation, the engineered COF triggers robust photodynamic therapy (PDT) and induces catastrophic lipid peroxidation, effectively driving cancer cells into ferroptosis. In vivo assessments confirm that this synergistic PDT‐ferroptosis strategy achieves potent tumor regression with minimal systemic toxicity. This work elucidates the critical role of specific active‐site engineering in ionic COFs and provides a paradigm for designing molecular photosensitizers for multi‐modal cancer therapy.