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Trichosanthin (TCS) as a class of ribosome\u2010inactivating proteins is widely studied in tumor treatment. However, the immunogenicity can induce the formation of ADA, which can cause hypersensitivity reactions and neutralize the efficacy of TCS, thus limiting its clinical application in cancer therapy. Here, a promising solution to this issue\u00a0is presented by co\u2010administration of the rapamycin nanoparticles and TCS. PEGylated rapamycin amphiphilic molecule\u00a0is designed and synthesized as a prodrug and a delivery carrier, which can self\u2010assemble into a nanoparticle system with encapsulation of free rapamycin, a hydrophobic drug. It\u00a0is found that co\u2010injection of the PEGylated rapamycin nanoparticles and TCS could mitigate the formation of anti\u2010TCS antibody via inducing durable immunological tolerance. Importantly, the combination of TCS and the rapamycin nanoparticles\u00a0has an enhanced effect on inhibit the growth of breast cancer. This work provides a promising approach for protein toxin\u2010based anticancer therapy and for promoting the clinical translation.<\/jats:p>","DOI":"10.1002\/smll.202303916","type":"journal-article","created":{"date-parts":[[2023,9,14]],"date-time":"2023-09-14T03:33:51Z","timestamp":1694662431000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Mitigation of Anti\u2010Drug Antibody Production for Augmenting Anticancer Efficacy of Therapeutic Protein via Co\u2010Injection of Nano\u2010Rapamycin"],"prefix":"10.1002","volume":"20","author":[{"given":"Ya","family":"Chang","sequence":"first","affiliation":[{"name":"School of Pharmacy Shanghai Jiao Tong University  Shanghai 200240 China"},{"name":"State Key Laboratory of Drug Research Shanghai Institute of Materia Medica Chinese Academy of Sciences  Shanghai 201203 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