Innovative applications and synergistic strategies for covalent organic frameworks in multimodal phototherapy.

Over the past few decades, the field of phototherapy has undergone a significant transition. Covalent organic frameworks (COFs), with their structural design, biocompatibility, and photostability, have emerged as key materials in phototherapy advancement. Photoactive COFs have demonstrated potential in treating various diseases. However, traditional single-modal COF-based phototherapy, relying on thermal imbalance and oxidative stress, struggles with complex diseases, limiting therapeutic efficacy. This review systematically summarizes the synergistic strategies and innovative applications of COFs in phototherapy from a multimodal perspective. It focuses on designs enhancing COF photoactivity, including topological structure transformation, bandgap structures, and chemical bonding modes. These optimized designs enhance photothermal conversion efficiency and reactive oxygen species (ROS) generation by fine-tuning the electronic structures and photophysical properties. The review emphasizes COF-based phototherapy combination strategies, including light-responsive delivery, photo-immunological activation, metabolic regulation, gas molecule release, starvation intervention, and biological modification. These multimodal and synergistic therapeutic systems promote complex disease treatment. Finally, it evaluates clinical translation challenges, including regulatory barriers, toxicological assessment, and metabolic fates, while outlining artificial intelligence (AI)-based design prospects in precision medicine and photo-vaccine development strategies for long-term immunotherapy. STATEMENT OF SIGNIFICANCE: This review highlights the transformative role of covalent organic frameworks (COFs) in advancing multimodal phototherapy, addressing critical limitations of traditional single-modal approaches. By systematically summarizing structural engineering strategies to enhance COF photoactivity-including, but not limited to, topological modulation, bandgap tuning, and stacking mode design-and integrating these with synergistic therapeutic systems (e.g., photo-responsive delivery, immune activation, and metabolic regulation), a comprehensive framework is provided for combating complex diseases. Notably, the work bridges material design with clinical translation, discussing regulatory and toxicological challenges while outlining the prospects of AI-driven precision medicine and photovaccines. This synthesis not only advances the fundamental understanding of COF-based phototherapy but also accelerates its transition from the lab to the clinic, offering novel solutions for cancer, infectious diseases, and beyond.