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SM-SERS can detect chemical information of single molecules without statistical averaging and has wide application in chemical analysis, nanoelectronics, biochemical sensing, etc. Recently, a series of unprecedented advances have been realized in science and application by SM-SERS, which has attracted the interest of various fields. In this review, we first elucidate the key concepts of SM-SERS, including enhancement factor (EF), spectral fluctuation, and experimental evidence of single-molecule events. Next, we systematically discuss advanced implementations of SM-SERS, including substrates with ultra-high EF and reproducibility, strategies to improve the probability of molecules being localized in hotspots, and nonmetallic and hybrid substrates. Then, several examples for the application of SM-SERS are proposed, including catalysis, nanoelectronics, and sensing. Finally, we summarize the challenges and future of SM-SERS. We hope this literature review will inspire the interest of researchers in more fields.<\/jats:p>","DOI":"10.3390\/s22134889","type":"journal-article","created":{"date-parts":[[2022,6,29]],"date-time":"2022-06-29T01:48:38Z","timestamp":1656467318000},"page":"4889","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":80,"title":["Single-Molecule Surface-Enhanced Raman Spectroscopy"],"prefix":"10.3390","volume":"22","author":[{"given":"Yuxuan","family":"Qiu","sequence":"first","affiliation":[{"name":"State Key Laboratory of Modern Optical Instrumentation, College of Optical Science & Engineering, Zhejiang University, Hangzhou 310027, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Cuifang","family":"Kuang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Modern Optical Instrumentation, College of Optical Science & Engineering, Zhejiang University, Hangzhou 310027, China"},{"name":"Ningbo Research Institute, Zhejiang University, Ningbo 315100, China"},{"name":"Collaborative Innovation Center of Extreme Optics, Shanxi University, Taiyuan 030006, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xu","family":"Liu","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Modern Optical Instrumentation, College of Optical Science & Engineering, Zhejiang University, Hangzhou 310027, China"},{"name":"Ningbo Research Institute, Zhejiang University, Ningbo 315100, China"},{"name":"Collaborative Innovation Center of Extreme Optics, Shanxi University, Taiyuan 030006, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3833-3113","authenticated-orcid":false,"given":"Longhua","family":"Tang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Modern Optical Instrumentation, College of Optical Science & Engineering, Zhejiang University, Hangzhou 310027, China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2022,6,29]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"501","DOI":"10.1038\/121501c0","article-title":"A new type of secondary radiation","volume":"121","author":"Raman","year":"1928","journal-title":"Nature"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"R1","DOI":"10.1088\/0031-9155\/45\/2\/201","article-title":"Prospects for in vivo Raman spectroscopy","volume":"45","author":"Hanlon","year":"2000","journal-title":"Phys. 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