Shattering the "golden armor": A natural supramolecular nanoplatform for optical virulence modulation and MRSA keratitis therapy.

Methicillin-resistant Staphylococcus aureus (MRSA) keratitis constitutes a formidable therapeutic impasse, driven by the convergence of the pathogen's intrinsic antioxidant "golden armor" (staphyloxanthin, STX) and the cornea's extrinsic physical barrier. Herein, we overcome these dual obstacles via carrier-free supramolecular nanotherapeutic (HB@GA), engineered through the co-assembly of the natural photosensitizer hypocrellin B (HB) and the bioactive glycyrrhizic acid (GA). This minimalist all-active design not only ensures 100% active payload but also enables deep corneal drug delivery via GA-enhanced membrane permeation. Upon 460 nm irradiation, the system executes a synchronous disarm-and-kill cascade, where the wavelength-specific photobleaching of STX optically strips the bacterial antioxidant defense, rendering the pathogen hypersensitive to concurrent reactive oxygen species storm generated by HB. Beyond potent sterilization, the bioactive GA component fundamentally reshapes the inflammatory microenvironment by inhibiting the HMGB1/TLR4 signaling axis, which shifts macrophage polarization from a pro-inflammatory M1 to a tissue-reparative M2 phenotype. In a murine keratitis model, the HB@GA nanoplatform combined with light treatment achieved rapid bacterial clearance and accelerated corneal reconstruction. By seamlessly integrating optical bio-intervention with bioactive supramolecular nanomedicine, this work establishes a promising "anti-infection and pro-repair" paradigm for addressing multidrug-resistant ocular pathologies.