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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\u201320) toward mammalian cells compared with the clinically approved amphotericin B (SI &amp;lt; 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\u2013pathogen lipid disparity as a promising paradigm for developing precision antifungal strategies.<\/jats:p>","DOI":"10.1021\/jacs.6c10086","type":"journal-article","created":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T06:02:23Z","timestamp":1787032943000},"page":"36969-36982","source":"Crossref","is-referenced-by-count":1,"title":["Iteratively Designed\nPhospholipid-Targeted Supramolecular\nSonosensitizers for Precision Treatment of Pulmonary Infections"],"prefix":"10.1021","volume":"148","author":[{"given":"Qian","family":"Li","sequence":"first","affiliation":[{"name":"Central China Normal University , , ,","place":["Wuhan, China, 430079"]},{"name":"Huazhong Agricultural University , , ,","place":["Wuhan, China, 430070"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yida","family":"Pang","sequence":"additional","affiliation":[{"name":"Central China Normal University , , ,","place":["Wuhan, China, 430079"]},{"name":"Huazhong Agricultural University , , ,","place":["Wuhan, China, 430070"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junhua","family":"Zhang","sequence":"additional","affiliation":[{"name":"Central China Normal University , , ,","place":["Wuhan, China, 430079"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanping","family":"Liu","sequence":"additional","affiliation":[{"name":"Zhongnan Hospital of Wuhan University, Wuhan University , , ,","place":["Wuhan, China, 430071"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hui","family":"Chen","sequence":"additional","affiliation":[{"name":"Huazhong University of Science and Technology , , ,","place":["Wuhan, China, 430030"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuting","family":"Wang","sequence":"additional","affiliation":[{"name":"Huazhong Agricultural University , , ,","place":["Wuhan, China, 430070"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Longcan","family":"Mei","sequence":"additional","affiliation":[{"name":"Central China Normal University , , ,","place":["Wuhan, China, 430079"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Le","family":"Tu","sequence":"additional","affiliation":[{"name":"Central China Normal University , , ,","place":["Wuhan, China, 430079"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3777-2245","authenticated-orcid":true,"given":"Junrong","family":"Li","sequence":"additional","affiliation":[{"name":"Central China Normal University , , ,","place":["Wuhan, China, 430079"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6519-7436","authenticated-orcid":true,"given":"Yao","family":"Sun","sequence":"additional","affiliation":[{"name":"Huazhong Agricultural University , , ,","place":["Wuhan, China, 430070"]},{"name":"Hubei Jiangxia Laboratory , ,","place":["Wuhan, China, 430020"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2026,8,18]]},"reference":[{"issue":"1","key":"2026090312104066600_cit1","doi-asserted-by":"publisher","first-page":"9125","DOI":"10.1038\/s41467-025-64171-x","article-title":"Molecular\nLandscape of the Fungal Plasma Membrane and\nImplications for Antifungal Action","volume":"16","author":"Jiang","year":"2025","journal-title":"Nat. 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Commun."},{"key":"2026090312104066600_cit5","doi-asserted-by":"publisher","DOI":"10.1002\/anie.202521135","article-title":"Fluorescent\nProbes Derived from the\nPolyene Class of Antifungal Drugs Reveal Distinct Localization Patterns\nand Resistance-Associated Vacuolar Sequestration in Candida Species","volume":"65","author":"Shbeta","year":"2026","journal-title":"Angew. Chem., Int. Ed."},{"issue":"6","key":"2026090312104066600_cit6","doi-asserted-by":"publisher","first-page":"3390","DOI":"10.1021\/acs.chemrev.0c00199","article-title":"Antifungal Drug\nResistance: Molecular Mechanisms in Candida albicans and Beyond","volume":"121","author":"Lee","year":"2021","journal-title":"Chem. Rev."},{"issue":"5","key":"2026090312104066600_cit7","doi-asserted-by":"publisher","first-page":"607","DOI":"10.1038\/s41564-022-01112-0","article-title":"Evolution\nof the Human Pathogenic Lifestyle in Fungi","volume":"7","author":"Rokas","year":"2022","journal-title":"Nat. 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Chem., Int. Ed."},{"key":"2026090312104066600_cit11","doi-asserted-by":"publisher","DOI":"10.1038\/s41587-025-02930-3","article-title":"Effective\nCombinatorial Antifungal Therapy using AHost Defense Peptide Mimic\nthat Self-assembles into Delivery Micelles","author":"Liu","year":"2026","journal-title":"Nat. Biotechnol."},{"issue":"10","key":"2026090312104066600_cit12","doi-asserted-by":"publisher","first-page":"202104384","DOI":"10.1002\/advs.202104384","article-title":"Photoinactivation\nof Catalase Sensitizes\nCandida albicans and Candida auris to ROS-Producing Agents and Immune\nCells","volume":"9","author":"Dong","year":"2022","journal-title":"Adv. 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Soc."},{"issue":"15","key":"2026090312104066600_cit21","doi-asserted-by":"publisher","DOI":"10.1002\/anie.202319966","article-title":"De Novo Designed Ru(II)\nMetallacycle as a Microenvironment-Adaptive Sonosensitizer and Sonocatalyst\nfor Multidrug-Resistant Biofilms Eradication","volume":"63","author":"Xu","year":"2024","journal-title":"Angew. Chem., Int. Ed."},{"issue":"7","key":"2026090312104066600_cit22","doi-asserted-by":"publisher","first-page":"2668","DOI":"10.1039\/D5QI00180C","article-title":"Heavy atom engineering of Ru(II) complex based sonosensitizers for\nenhancing antifungal therapy","volume":"12","author":"Li","year":"2025","journal-title":"Inorg. Chem. Front."},{"issue":"52","key":"2026090312104066600_cit23","doi-asserted-by":"publisher","first-page":"48072","DOI":"10.1021\/jacs.5c14960","article-title":"An O2-Independent Copper(II) Phototherapeutic Agent for\nPhotoactivating H2O2 to Enhance Antitumor Immunotherapy","volume":"147","author":"Zhao","year":"2025","journal-title":"J. Am. Chem. Soc."},{"issue":"3","key":"2026090312104066600_cit24","doi-asserted-by":"publisher","first-page":"1275","DOI":"10.1021\/jacs.6b11846","article-title":"Metalloporphyrin-Encapsulated\nBiodegradable Nanosystems for Highly Efficient Magnetic Resonance\nImaging-Guided Sonodynamic Cancer Therapy","volume":"139","author":"Huang","year":"2017","journal-title":"J.\nAm. Chem. Soc."},{"issue":"50","key":"2026090312104066600_cit25","doi-asserted-by":"publisher","first-page":"34669","DOI":"10.1021\/jacs.4c13022","article-title":"Sonodynamic Nano-LYTACs\nReverse Tumor Immunosuppressive Microenvironment for Cancer Immunotherapy","volume":"146","author":"Xu","year":"2024","journal-title":"J. Am. Chem. Soc."},{"issue":"37","key":"2026090312104066600_cit26","doi-asserted-by":"publisher","first-page":"25764","DOI":"10.1021\/jacs.4c08278","article-title":"Sonoinduced\nTumor Therapy and Metastasis Inhibition by a Ruthenium Complex with\nDual Action: Superoxide Anion Sensitization and Ligand Fracture","volume":"146","author":"He","year":"2024","journal-title":"J. Am. Chem. Soc."},{"issue":"29","key":"2026090312104066600_cit27","doi-asserted-by":"publisher","first-page":"25622","DOI":"10.1021\/jacs.5c06488","article-title":"Nanoscale Donor-Acceptor\nCovalent Organic Frameworks for Mitochondria-Targeted\nSonodynamic Therapy and Antitumor Immunity","volume":"147","author":"Liu","year":"2025","journal-title":"J. Am. Chem. Soc."},{"issue":"7","key":"2026090312104066600_cit28","doi-asserted-by":"publisher","DOI":"10.1002\/anie.202521145","article-title":"Ruthenium-Based Sonoafterglow\nProbes for Tumor-Specific Theranostics","volume":"65","author":"Wang","year":"2026","journal-title":"Angew.\nChem., Int. Ed."},{"issue":"18","key":"2026090312104066600_cit29","doi-asserted-by":"publisher","DOI":"10.1002\/anie.202301831","article-title":"Construction\nof Multiform Hollow-Structured Covalent Organic Frameworks via a Facile\nand Universal Strategy for Enhanced Sonodynamic Cancer Therapy","volume":"62","author":"Liu","year":"2023","journal-title":"Angew. Chem., Int. Ed."},{"key":"2026090312104066600_cit30","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2209904119","article-title":"Long wavelength\u2013emissive Ru(II)\nmetallacycle\u2013based photosensitizer assisting in vivo bacterial\ndiagnosis and antibacterial treatment","volume":"119","author":"Xu","year":"2022","journal-title":"Proc.\nNatl. Acad. Sci. U. S. A."},{"issue":"8059","key":"2026090312104066600_cit31","doi-asserted-by":"publisher","first-page":"676","DOI":"10.1038\/s41586-025-08833-2","article-title":"Supramolecular docking\nstructure determination of alkyl-bearing molecules","volume":"640","author":"Wu","year":"2025","journal-title":"Nature"},{"issue":"5","key":"2026090312104066600_cit32","doi-asserted-by":"publisher","first-page":"653","DOI":"10.1038\/s41557-025-01750-x","article-title":"Supramolecular coordination\ncages as crystalline sponges through a symmetry mismatch strategy","volume":"17","author":"He","year":"2025","journal-title":"Nat. Chem."},{"issue":"1","key":"2026090312104066600_cit33","doi-asserted-by":"publisher","first-page":"63","DOI":"10.1039\/D5CS00734H","article-title":"Supramolecular\ndyes:\nadvancing precision medicine through molecular engineering","volume":"55","author":"Li","year":"2026","journal-title":"Chem. Soc. Rev."},{"issue":"18","key":"2026090312104066600_cit34","doi-asserted-by":"publisher","DOI":"10.1002\/anie.202401136","article-title":"Pt(II)\/Pd(II)-Based\nMetallosupramolecular Architectures as Light Harvesting Systems and\ntheir Applications","volume":"63","author":"Bokotial","year":"2024","journal-title":"Angew. Chem., Int. Ed."},{"issue":"2","key":"2026090312104066600_cit35","doi-asserted-by":"publisher","DOI":"10.1002\/anie.202414089","article-title":"Metallo-Supramolecular\nHelicates as Surface-Enhanced\nRaman Scattering (SERS) Substrates with High Tailorability","volume":"64","author":"Song","year":"2024","journal-title":"Angew. Chem., Int. 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Soc."},{"issue":"12","key":"2026090312104066600_cit38","doi-asserted-by":"publisher","first-page":"893","DOI":"10.1038\/s41570-024-00657-4","article-title":"Assembling a new generation of radiopharmaceuticals\nwith supramolecular theranostics","volume":"8","author":"Moreno-Alca\u0301ntar","year":"2024","journal-title":"Nat. Rev.\nChem."},{"issue":"8","key":"2026090312104066600_cit39","doi-asserted-by":"publisher","first-page":"1174","DOI":"10.1021\/acs.accounts.4c00031","article-title":"Supramolecular Coordination\nComplexes for Synergistic Cancer Therapy","volume":"57","author":"Li","year":"2024","journal-title":"Acc.\nChem. Res."},{"issue":"4","key":"2026090312104066600_cit40","doi-asserted-by":"publisher","first-page":"1174","DOI":"10.1039\/C7CS00594F","article-title":"Supramolecular Photosensitizers Rejuvenate\nPhotodynamic\nTherapy","volume":"47","author":"Li","year":"2018","journal-title":"Chem. Soc. Rev."},{"issue":"24","key":"2026090312104066600_cit41","doi-asserted-by":"publisher","first-page":"7730","DOI":"10.1021\/jacs.8b04929","article-title":"Highly Emissive\nSelf-Assembled BODIPY-Platinum\nSupramolecular Triangles","volume":"140","author":"Zhou","year":"2018","journal-title":"J. Am. Chem. Soc."},{"issue":"25","key":"2026090312104066600_cit42","doi-asserted-by":"publisher","first-page":"10143","DOI":"10.1002\/anie.201915055","article-title":"Luminescent Metallacycle-Cored Liquid Crystals Induced by Metal Coordination","volume":"59","author":"Chen","year":"2020","journal-title":"Angew. Chem., Int. Ed."},{"issue":"5","key":"2026090312104066600_cit43","doi-asserted-by":"publisher","DOI":"10.1002\/anie.202110048","article-title":"Design of\na Metallacycle-Based Supramolecular Photosensitizer for In Vivo Image-Guided\nPhotodynamic Inactivation of Bacteria","volume":"61","author":"Xu","year":"2022","journal-title":"Angew.\nChem., Int. Ed."},{"issue":"26","key":"2026090312104066600_cit44","doi-asserted-by":"publisher","first-page":"8378","DOI":"10.1002\/chem.201301348","article-title":"Transporting\nand Shielding Photosensitisers by Using Water-Soluble Organometallic\nCages: A New Strategy in Drug Delivery and Photodynamic Therapy","volume":"19","author":"Therrien","year":"2013","journal-title":"Chem. Eur. J."},{"key":"2026090312104066600_cit45","doi-asserted-by":"publisher","first-page":"369","DOI":"10.1021\/ar040153h","article-title":"Coordination Assembliesfroma\nPd(II)-Cornered Square Complex","volume":"38","author":"Fujita","year":"2005","journal-title":"Acc. Chem. Res."},{"issue":"28","key":"2026090312104066600_cit46","doi-asserted-by":"publisher","first-page":"12825","DOI":"10.1021\/jacs.2c03895","article-title":"Self-Assembled Metallacage\nwith Second Near-Infrared Aggregation-Induced\nEmission for Enhanced Multimodal Theranostics","volume":"144","author":"Qin","year":"2022","journal-title":"J. Am. Chem. 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