Overcoming gentamicin resistance in MRSA by a polyphenol-assembled nanoplatform

OG/ICG, an intelligent nano-prodrug, is engineered by conjugating OPC with GEN, and ICG loading. • OG/ICG remains inert systemically but switches charge and dissociates in acidic infections. • The efficacy of GEN against MRSA was restored through the synergistic action of OPC and photothermia. • Combined chemical, physical, and targeting actions enable full eradication of GEN-resistant MRSA. The waning efficacy of aminoglycosides, like gentamicin (GEN), against methicillin-resistant Staphylococcus aureus (MRSA) necessitates strategies that transcend the protracted pipeline of de novo antibiotic discovery. Herein, we present a “resensitization” strategy enabled by a carrier-free, supramolecular nano-prodrug (OG/ICG NPs), engineered via the oxidative co-assembly of oligomeric proanthocyanidin (OPC) and GEN, followed by indocyanine green (ICG) loading. Distinct from conventional inert delivery systems, this bioactive platform remains stable physiologically but undergoes charge reversal and rapid dissociation within the acidic infection microenvironment. Mechanistically, the released OPC functions as a potent resistance-breaking adjuvant by disrupting cell wall integrity and inhibiting efflux pumps, thereby facilitating massive intracellular GEN accumulation. Under near-infrared (NIR) irradiation, localized hyperthermia synergizes with this chemical attack to compromise membrane permeability and trigger pronounced metabolic collapse, characterized by disrupted fatty acid degradation and ATP depletion, as revealed by both transcriptomic and phenotypic profiling. Furthermore, the nanoplatform promotes regulating macrophage polarization from M1 to M2 phenotype, accelerating abscess resolution and tissue regeneration. This work establishes a robust, dual-responsive paradigm that not only eradicates resistant pathogens through metabolic and structural disruption but also orchestrates an immune-favorable microenvironment for wound healing.