Tetrasulfide-bridged virus-like particles enable host-sparing cascade membrane-metabolic disruption for...

Drug-resistant bacterial keratitis remains difficult to treat because anatomical barriers and biofilm-associated tolerance restrict antibacterial access and efficacy. Intensifying bactericidal activity can enhance bacterial clearance, but may also cause nonspecific host injury and disrupt stromal homeostasis. Thus, effective therapy requires a strategy that redirects antibacterial action from bacterial surface killing to intracellular intervention without perturbing the corneal stromal microenvironment. Herein, we developed AuNR@vTSMS-DLYS, a virus-mimetic spiky nanoplatform that couples bacterial barrier breaching with intracellular redox-metabolic disruption to achieve bacteria-selective eradication. Its spiky nanotopography enhances biofilm contact and disrupts membrane barriers, driving antibacterial intervention from the bacterial exterior into the intracellular space. Within the reductive bacterial intracellular milieu, the tetrasulfide-bridged framework is cleaved, glutathione is depleted, and sulfur overload is induced, thereby undermining intracellular bacterial defenses. Mild near-infrared irradiation provides spatially controllable photothermal amplification, further enhancing interfacial disruption, deep penetration, and intracellular damage. AuNR@vTSMS-DLYS achieved > 99% bacterial clearance in vitro and reduced corneal bacterial survival to 3.1% in a multidrug-resistant Pseudomonas aeruginosa keratitis mouse model, while restoring stromal thickness from 280 μm to 120 μm. This study establishes a host-sparing intracellular resistance-disarming strategy that redirects antibacterial action from bacterial external barriers to intracellular defense systems, offering a new design principle for precision treatment of drug-resistant infections.