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However, the application of liposomes encounters major challenges due to the knowledge gaps in their in vivo delivery process. Immunoglobulin M (IgM) displays both pervasiveness and complexity in regulating the biological functions as well as eliciting adverse effects of liposomes. Understanding, mitigating, and exploiting the duality of IgM are prerequisites for achieving various biomedical applications of liposomes. In this review, the intricate relationship between liposomes and their biological environments has been summarized, with an emphasis on the regulatory effects of IgM on in vivo performance of liposomes. 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