A sequential mucus-penetrating and pH/ROS-responsive organosilica nanoplatform for co-delivery of natural antibiotics to combat drug resistant lung infection

The treatment of bacterial pneumonia remains severely constrained by the complex pulmonary physiopathological barriers, including the mucus layer and biofilm matrix, which restrict the effective delivery of antibiotics. Moreover, the acidic and reactive oxygen species (ROS)-rich microenvironment at the infection site further impairs the controlled release of therapeutic agents. To overcome this multifaceted challenge, we developed a dual-responsive nanoplatform (PTCSeM) based on diselenide-bridged mesoporous organosilica nanoparticles (SeM) with a design rationale that directly counters each barrier: surface functionalization with chitosan and ROS-labile mPEG-TK enables sequential mucus penetration, pH-responsive drug release, and ROS-accelerated degradation. This nanoplatform co-loaded two natural antibiotics, honokiol (HK) and carvacrol (CAL), enabling targeted drug delivery within the acidic infection site. Notably, ROS-mediated degradation of the nanocarrier facilitated the synergistic integration of antibacterial, anti-inflammatory, and antioxidant effects. In vivo evaluations demonstrated that PTCSeM@HK-CAL markedly reduced bacterial loads in the lungs of animal models infected with multidrug-resistant pathogens. It also exerted robust therapeutic effects by modulating inflammatory cytokine expression and alleviating oxidative stress. Collectively, this dual-stimuli-responsive organosilica-based nanoplatform for the co-delivery of dual antibiotics presents a promising integrated strategy for treating drug-resistant bacterial pneumonia, offering enhanced mucus penetration, stimulus-responsive release, deep biofilm clearance, and potent antibacterial and anti-inflammatory activities.