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Despite their effectiveness, ADCs can face limitations due to acquired resistance and potential side effects. Objectives: This study focuses on advances in various ADC components to improve both the efficacy and safety of these agents, and includes the analysis of several novel ADC formats. This work assesses whether the unique features of VHHs\u2014such as their small size, enhanced tissue penetration, stability, and cost-effectiveness\u2014make them a viable alternative to conventional antibodies for ADCs and reviews their current status in ADC development. Methods: Following PRISMA guidelines, this study focused on VHHs as components of ADCs, examining advancements and prospects from 1 January 2014 to 30 June 2024. Searches were conducted in PubMed, Cochrane Library, ScienceDirect and LILACS using specific terms related to ADCs and single-domain antibodies. Retrieved articles were rigorously evaluated, excluding duplicates and non-qualifying studies. The selected peer-reviewed articles were analyzed for quality and synthesized to highlight advancements, methods, payloads, and future directions in ADC research. Results: VHHs offer significant advantages for drug conjugation over conventional antibodies due to their smaller size and structure, which enhance tissue penetration and enable access to previously inaccessible epitopes. Their superior stability, solubility, and manufacturability facilitate cost-effective production and expand the range of targetable antigens. Additionally, some VHHs can naturally cross the blood\u2013brain barrier or be easily modified to favor their penetration, making them promising for targeting brain tumors and metastases. Although no VHH\u2013drug conjugates (nADC or nanoADC) are currently in the clinical arena, preclinical studies have explored various conjugation methods and linkers. Conclusions: While ADCs are transforming cancer treatment, their unique mechanisms and associated toxicities challenge traditional views on bioavailability and vary with different tumor types. Severe toxicities, often linked to compound instability, off-target effects, and nonspecific blood cell interactions, highlight the need for better understanding. Conversely, the rapid distribution, tumor penetration, and clearance of VHHs could be advantageous, potentially reducing toxicity by minimizing prolonged exposure. These attributes make single-domain antibodies strong candidates for the next generation of ADCs, potentially enhancing both efficacy and safety.<\/jats:p>","DOI":"10.3390\/cancers16152681","type":"journal-article","created":{"date-parts":[[2024,7,29]],"date-time":"2024-07-29T09:50:05Z","timestamp":1722246605000},"page":"2681","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":40,"title":["Single-Domain Antibodies as Antibody\u2013Drug Conjugates: From Promise to Practice\u2014A Systematic Review"],"prefix":"10.3390","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0044-0615","authenticated-orcid":false,"given":"V\u00edctor Manuel","family":"Medina P\u00e9rez","sequence":"first","affiliation":[{"name":"Molecular Oncology Group, Instituto de Investigaci\u00f3n Sanitaria Arag\u00f3n (IIS Arag\u00f3n), 50009 Zaragoza, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2672-5790","authenticated-orcid":false,"given":"Marta","family":"Baselga","sequence":"additional","affiliation":[{"name":"Molecular Oncology Group, Instituto de Investigaci\u00f3n Sanitaria Arag\u00f3n (IIS Arag\u00f3n), 50009 Zaragoza, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0136-1049","authenticated-orcid":false,"given":"Alberto J.","family":"Schuhmacher","sequence":"additional","affiliation":[{"name":"Molecular Oncology Group, Instituto de Investigaci\u00f3n Sanitaria Arag\u00f3n (IIS Arag\u00f3n), 50009 Zaragoza, Spain"},{"name":"Fundaci\u00f3n Aragonesa para la Investigaci\u00f3n y el Desarrollo (ARAID), 50018 Zaragoza, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,7,27]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"20","DOI":"10.1038\/nrc.2016.108","article-title":"Cancer Nanomedicine: Progress, Challenges and Opportunities","volume":"17","author":"Shi","year":"2017","journal-title":"Nat. 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