Harnessing the dual role of reactive oxygen species in bacterial infection: Therapeutic opportunities for controlled release and targeted modulation.

Abstract

Reactive oxygen species (ROS) act as a double-edged sword in bacterial infections, possessing both potent antimicrobial effectors and sophisticated signaling rheostats that dictate the trajectory of host-pathogen interactions. Spatiotemporal concentration gradients of ROS at the infection sites dynamically remodel the host-pathogen interface, cellular adhesion, extracellular matrix architecture, and bacterial virulence programs. The concentration-dependent redox microenvironment serves as a critical determinant of infection progression and provides a unique physicochemical trigger for the design of next-generation therapeutic platforms. This review comprehensively elucidates the multifaceted roles of ROS during bacterial adhesion and invasion and further explores precise intervention strategies targeting the ROS-related microenvironments. These strategies comprise three interrelated levels: (i) pharmacological modulation of host NADPH oxidase activity and adhesion molecules to maintain redox equilibrium and prevent pathogen invasion; (ii) metabolic reactivation and targeting of antioxidant genes to increase bacterial susceptibility to endogenous ROS, thereby overcoming bacterial tolerance and resistance; and (iii) the development of ROS-responsive biomaterials, including borate ester- and thioketal-based nanocarriers, hierarchically structured hydrogels, and nanozyme systems, which facilitate on-demand drug release, spatiotemporal bidirectional ROS regulation (generation versus scavenging), and adaptation to specific lesions in chronic wounds, biofilms, and respiratory infections. Additionally, we address significant translational challenges, such as off-target oxidative damage, response threshold selectivity, and comprehensive biosafety evaluation using specific probes and oxidative biomarkers. Together, these ROS-targeted interventions offer a versatile and translatable platform for the development of next-generation anti-infective therapies. STATEMENT OF SIGNIFICANCE: ROS exert dual, context-dependent effects at the host-pathogen interface, which act not only as antimicrobial effectors but also as key signaling mediators that govern bacterial adhesion, invasion, biofilm formation and host immunity. ROS mediate bidirectional host-bacteria crosstalk that shapes infection outcomes via tightly regulated concentration and spatiotemporal dynamics. In the review, we present an integrated therapeutic framework that combines host-directed redox modulation, bacterial ROS sensitization, and engineered intelligent biomaterials. We highlight ROS-responsive carriers specifically designed for heterogeneous infection microenvironments as well as materials capable of spatiotemporally controlled, bidirectional ROS regulation. By integrating redox biology with materials design, this work advances precision anti-infective strategies to address the global challenge of antimicrobial resistance.