Iteratively DesignedPhospholipid-Targeted SupramolecularSonosensitizers for Precision Treatment of Pulmonary Infections

Abstract Fungal infections represent a significant global health threat, exacerbated by the scarcity of new therapeutic options, increasing drug resistance, and host toxicity. Sonodynamic therapy (SDT) offers a promising approach to overcoming antimicrobial resistance by enabling the localized generation of cytotoxic reactive oxygen species (ROS) within deep-seated lesions. Nevertheless, reports of SDT for in vivo antifungal treatment remain scarce, largely due to suboptimal ROS generation efficiency, poor biofilm penetration, and a lack of fungal specificity. Herein, we report the iterative design of RuB-C12, a phospholipid-targeted supramolecular sonosensitizer assembled via molecular engineering of ligand and acceptor building blocks into a Ru(II) metallocycle. Upon ultrasound activation, RuB-C12 markedly enhances ROS production while simultaneously improving the fungal membrane affinity and biofilm penetration. Mechanistic studies reveal that RuB-C12 effectively eradicates pathogenic yeasts by disrupting phospholipid phase transitions and perturbing intracellular redox homeostasis. Notably, RuB-C12 demonstrates a superior selectivity index (SI = 10–20) toward mammalian cells compared with the clinically approved amphotericin B (SI < 5). In murine models of wound and pulmonary Candida albicans infections as well as in clinical specimens, RuB-C12-mediated SDT significantly reduces fungal burden without inducing observable systemic toxicity. Collectively, this work highlights host–pathogen lipid disparity as a promising paradigm for developing precision antifungal strategies.