Tailored photonic bodyguards for methylene blue regeneration and enhanced photodynamic therapy

Bioreduction-induced quenching of methylene blue (MB), particularly under photoexcitation, leads to a primary contradiction between the high ROS yield (∼50%) and its unsatisfactory clinical photodynamic therapy efficiency. Current strategies, such as nano-encapsulation or ionic supplementation, have potential to improve the photocytotoxicity via spatial isolation or radical conversion. However, these approaches fail to reverse the reduction quenching within the bio-system, which remains a significant challenge in MB regeneration and oxygen conservation. Herein, we propose a "photonic bodyguard" strategy to protect MB's photon utilization and ROS generation efficiency via the strategic introduction of specific electron acceptors. For example, thymoquinone (TQ) preserves 100% of MB's absorbance and achieves a 4.9-fold photo-induced ROS output in the presence of bio-reductants. Consequently, TQ-assisted MB demonstrates superior potency in both tumor cell killing (1.8-fold) and antibacterial capability. Spectral and electrochemical characterization reveal that electron withdrawing sites and a more positive reduction potential (>-0.69 V) are crucial for capturing electrons from leucoMB, thereby replacing oxygen consumption during the MB regeneration cycle. This work establishes a type of electron acceptor protector strategy to overcome the bio-reduction limitations of MB, aiming to facilitate its clinical phototherapeutic advancement.