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Enhancing the permeability across the physical barriers, including lipopolysaccharide (LPS) and extracellular polymeric substances (EPS), while simultaneously preventing drug resistance, remains a major challenge. To address this issue, we developed a novel biotin\u2010conjugated cationic photosensitizer (PS), ACR\u2010DM\u2010Bio. It not only effectively binds to the bacterial outer membrane and EPS via electrostatic interactions but also facilitates active uptake through the biotin transport system. This dual mechanism promotes penetration through the physical barriers and destroys the outer membrane. Moreover, ACR\u2010DM\u2010Bio competitively disrupts biotin\u2010dependent metabolism and inhibits fatty acid biosynthesis, thereby compromising outer membrane integrity. Besides, this metabolic interference further hinders the tricarboxylic acid (TCA) cycle, severely disrupting energy metabolism and biosynthetic precursor supply. This three\u2010pronged strategy could efficiently overcome bacterial resistance evolution and prevent biofilm recurrence. In a murine biofilm infection model, ACR\u2010DM\u2010Bio\u2013mediated photodynamic therapy (PDT) not only completely cleared biofilms but also promoted tissue repair by modulating inflammation and angiogenesis, outperforming the conventional antibiotic polymyxin B. This work not only presents a highly promising candidate for treating MDR bacterial infections, but also provides theoretical guidance for the rational design of next\u2010generation antimicrobial PS.<\/jats:p>","DOI":"10.1002\/smll.73597","type":"journal-article","created":{"date-parts":[[2026,4,30]],"date-time":"2026-04-30T08:31:48Z","timestamp":1777537908000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Combating Bacterial Drug Resistance via Dual\u2010Mechanism Drive Penetration and Triple\u2010Approach Metabolic Disruption"],"prefix":"10.1002","volume":"22","author":[{"given":"Xu","family":"Wang","sequence":"first","affiliation":[{"name":"Key Laboratory of Green Chemistry and Technology College of Chemistry Ministry of Education Sichuan University  Chengdu P. R. 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