Water-Soluble Chlorophyll Proteins as Biocompatible Photosensitizers for Photodynamic Therapy to Combat Antibiotic Resistance and Biofilm Through Disrupting Bacterial Membranes

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The escalating crisis of antibiotic resistance and biofilm-associated infections urgently demands therapeutic strategies with distinct mechanisms of action. Antibacterial photodynamic therapy (abPDT) offers a promising alternative, yet its clinical translation is often limited by the poor solubility, low biocompatibility, or complex delivery requirements of conventional photosensitizers (PSs). Here, we report the application of recombinant water-soluble chlorophyll proteins (WSCPs) from the Brassicaceae family as fully natural, self-contained PSs for abPDT. WSCP forms exceptionally stable tetrameric complexes with chlorophylls, providing outstanding water solubility, high photostability, negligible dark toxicity, and food-grade biocompatibility. Upon 660 nm light irradiation, WSCP-mediated abPDT achieves broad-spectrum killing of clinically relevant Gram-positive (including methicillin-resistant Staphylococcus aureus, MRSA) and Gram-negative bacteria and effectively disrupts mature biofilms. Mechanistically, WSCP adheres to bacterial surfaces and generates singlet oxygen in situ, causing rapid membrane permeabilization, leakage of intracellular contents, and cell death, through a resistance-evading, physical mode of action. In a murine MRSA-infected wound model, a single topical application of WSCP followed by light exposure significantly reduces bacterial burden, suppresses inflammation, accelerates tissue regeneration, and promotes wound closure without observable toxicity. This work establishes WSCP-based abPDT as a safe, simple, and highly effective platform to combat antibiotic-resistant and biofilm-associated infections.