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Conventional antimicrobial therapy is limited by inaccurate pathogen identification, off-target effect, and increasing resistance, for which bioorthogonal chemistry offers a promising solution. Bioorthogonal chemistry comprises rapid and selective chemical reactions performed in biological environments with minimal interference with endogenous processes. This technique has been widely used in biomarkers, drug delivery, etc., due to its biocompatibility and targeting ability. In antibacterial applications, metabolic or affinity-based installation of abiotic chemical handles can decouple bacterial recognition from subsequent imaging or therapeutic recruitment. This review summarizes bioorthogonal strategies for bacterial detection, targeted drug delivery, light-responsive therapy, and localized prodrug activation and provides an application-driven framework for selecting reaction pairs. These approaches offer high chemical selectivity, covalent target retention, and modular integration with diverse diagnostic and therapeutic cargos, but their performance remains constrained by bacterial metabolic heterogeneity, reagent stability, tissue and biofilm transport, multicomponent pharmacokinetics, and long-term biosafety. Future progress will depend on faster and more biocompatible reaction design, standardized in vivo evaluation, scalable manufacturing, and clinically practical delivery or activation methods. By linking bacterial chemical labeling with therapeutic recruitment or activation, bioorthogonal chemistry provides a versatile framework for precision antibacterial therapy.<\/jats:p>","DOI":"10.1021\/acsbiomaterials.6c00948","type":"journal-article","created":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T05:02:49Z","timestamp":1790830969000},"source":"Crossref","is-referenced-by-count":0,"title":["Application of Bioorthogonal Chemistry in Targeted Antibacterial Therapy: Choosing the Right Chemistry"],"prefix":"10.1021","author":[{"given":"Qianyou","family":"Yang","sequence":"first","affiliation":[{"name":"West China Hospital of Stomatology, Sichuan University , , , ,","place":["Chengdu, Sichuan, China, 610041"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hanfei","family":"Li","sequence":"additional","affiliation":[{"name":"West China Hospital of Stomatology, Sichuan University , , , ,","place":["Chengdu, Sichuan, China, 610041"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jie","family":"Zhou","sequence":"additional","affiliation":[{"name":"West China Hospital of Stomatology, Sichuan University , , , ,","place":["Chengdu, Sichuan, China, 610041"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xu","family":"Wang","sequence":"additional","affiliation":[{"name":"West China Hospital of Stomatology, Sichuan University , , , ,","place":["Chengdu, Sichuan, China, 610041"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhou","family":"Zhu","sequence":"additional","affiliation":[{"name":"West China Hospital of Stomatology, Sichuan University , , , ,","place":["Chengdu, Sichuan, China, 610041"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6812-7356","authenticated-orcid":true,"given":"Xin","family":"Zhang","sequence":"additional","affiliation":[{"name":"West China Hospital of Stomatology, Sichuan University , , , ,","place":["Chengdu, Sichuan, China, 610041"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenjia","family":"Xie","sequence":"additional","affiliation":[{"name":"West China Hospital of Stomatology, Sichuan University , , , ,","place":["Chengdu, Sichuan, China, 610041"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1717-5782","authenticated-orcid":true,"given":"Junyu","family":"Chen","sequence":"additional","affiliation":[{"name":"West China Hospital of Stomatology, Sichuan University , , , ,","place":["Chengdu, Sichuan, China, 610041"]},{"name":"Lee Kong Chian School of Medicine, Nanyang Technological University , ,","place":["Singapore, 636921"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0386-8262","authenticated-orcid":true,"given":"Xibo","family":"Pei","sequence":"additional","affiliation":[{"name":"West China Hospital of Stomatology, Sichuan University , , , ,","place":["Chengdu, Sichuan, China, 610041"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liao","family":"Wang","sequence":"additional","affiliation":[{"name":"West China Hospital of Stomatology, Sichuan University , , , ,","place":["Chengdu, Sichuan, China, 610041"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hao","family":"Feng","sequence":"additional","affiliation":[{"name":"West China Hospital of Stomatology, Sichuan University , , , ,","place":["Chengdu, Sichuan, China, 610041"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2026,9,30]]},"reference":[{"key":"2026100101011294800_cit1","doi-asserted-by":"publisher","first-page":"1199","DOI":"10.1016\/S0140-6736(24)01867-1","article-title":"Global burden of bacterial antimicrobial resistance 1990\u20132021: a systematic analysis with forecasts to 2050","volume":"404","author":"GBD 2021 Antimicrobial Resistance Collaborators","year":"2021","journal-title":"Lancet"},{"key":"2026100101011294800_cit2","volume-title":"Antimicrobial resistance: accelerating national and global responses EB154\/13","author":"World Health Organization","year":"2023"},{"key":"2026100101011294800_cit3","doi-asserted-by":"publisher","DOI":"10.1136\/bmj-2024-082681","article-title":"Antimicrobial use and resistance","volume":"391","author":"Reza","year":"2025","journal-title":"BMJ"},{"key":"2026100101011294800_cit4","doi-asserted-by":"publisher","DOI":"10.1016\/j.jconrel.2025.114204","article-title":"Nanotechnology-based approaches to tackle bacterial infections","volume":"387","author":"Savadi","year":"2025","journal-title":"J. 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