Covalent Organic Frameworks as Next-Generation Photosensitizers: Mechanistic Underpinnings and Emerging Advances in Antimicrobial Photodynamic Therapy.

Abstract

Antimicrobial photodynamic therapy (aPDT) offers a non-antibiotic strategy for combating drug-resistant and biofilm-associated infections, but conventional photosensitizers are limited by aggregation, poor targeting, hypoxia, and insufficient biofilm penetration. Covalent organic frameworks (COFs) provide structurally programmable platforms that can organize photoactive units, modulate excited-state evolution, regulate reactive oxygen species (ROS) generation, and integrate bacterial targeting or microenvironment-responsive functions. This review examines COF-based aPDT from a structure-photophysics-ROS-biological response perspective. We discuss the structural identity of COF-based platforms, core photodynamic mechanisms, photoactive building blocks, and enhancement strategies including metal coupling, targeting engineering, responsive release, photothermal assistance, and multimodal therapy. Current challenges, including mechanistic over-attribution, biofilm-relevant validation, oxygen dependence, stability, biosafety, and standardization, are critically analyzed. Finally, we highlight mechanism-guided design and translational evaluation as key requirements for advancing COF-based aPDT toward clinically relevant antimicrobial applications.