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Herein, we introduced a reversible chemical cross\u2010linking strategy to engineer protein antigens, which can be tracelessly removed upon antigen\u2010presenting cell (APC) uptake and cellular reduction. The chemically cross\u2010linked antigen proteins presented significantly enhanced uptake and epitope presentation by APC. We applied this strategy to monkeypox virus antigens A29L and A35R to construct dual\u2010antigen subunit vaccines. Our results revealed that chemical cross\u2010linking was robust enough to improve both proteins' APC uptake and lymph node accumulation, with each protein being chemically cross\u2010linked and administered separately. In vivo validation revealed that the chemical cross\u2010linking of the two antigen proteins improved immune responses, with increases in antigen\u2010specific antibody and live virus\u2010neutralizing antibody production. Monkeypox virus challenge experiments revealed that dual\u2010antigen vaccines prepared via the chemical cross\u2010linking strategy mitigated tissue damage, reduced the virus load, and extended mouse survival, which proved that the chemical cross\u2010linking strategy is valuable for protein\u2010based subunit vaccine development. In consideration of the current threats from the monkeypox virus and potential future emerging pathogens, the chemical cross\u2010linking strategy provide powerful tools.<\/jats:p>","DOI":"10.1002\/mco2.70045","type":"journal-article","created":{"date-parts":[[2025,1,8]],"date-time":"2025-01-08T04:16:05Z","timestamp":1736309765000},"source":"Crossref","is-referenced-by-count":5,"title":["Chemical cross\u2010linking facilitates antigen uptake and presentation and provides improved protection from Mpox with a dual\u2010antigen subunit vaccine"],"prefix":"10.1002","volume":"6","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7802-5094","authenticated-orcid":false,"given":"Long","family":"Chen","sequence":"first","affiliation":[{"name":"Department of Pharmacy Peking University Third Hospital Cancer Center Peking University Third Hospital  Beijing 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