Fig 1: Exosome‐mediated lectin pathway of complement system enhances platelet destruction and immune responses through the transportation of MBL2, FCN2, and CFP proteins. A). Proteomic analysis of the BM plasma and plasma‐derived exosomes from individuals with primary immune thrombocytopenia. GO enrichment analysis was performed on the upregulated exosomal proteins in BM plasma samples from patients with ITP. BP, biological process; CC, cellular component; MF, molecular function. B). Volcano plots were used to display the selected upregulated proteins in exosomes from the BM plasma samples of patients with ITP compared to controls (i). A schematic overview of the complement pathways is presented, highlighting the master regulators of the complement system (ii). The differentially upregulated proteins, FCN2, MBL2, and CFP, are shown in red. The complement system serves as a pattern recognition and effector system for innate immunity and is capable of activation through the classical pathway by recognizing antibody clusters, the lectin pathway by sensing carbohydrate signatures, and the alternative pathway via the tick‐over mechanism. C). Immunofluorescence staining was performed on tumor‐adjacent liver tissue from patients diagnosed with human hepatocellular carcinoma (HCC). Hepatocyte marker (albumin), endothelial marker (CD31), Kupffer/macrophage marker (CD68), and selected proteins (CFP, MBL2, and FCN2) were assayed using immunofluorescence staining. D). Quantification of FCN2, MBL2, and CFP mRNA expression in the control and pseudovirus‐treated groups. P value significance represented by *, <0.05; **, <0.01; ***, <0.001; ****, <0.0001. E). Experimental methodology for examining the distribution of liver‐derived exosomes. Summary graphs showing the proportion of tdTomato+ cells in different tissues (thymus [normal, n = 3; AIH, n = 3], BM [normal, n = 3; AIH, n = 3], spleen [normal, n = 3; AIH, n = 3], PB [normal, n = 3; AIH, n = 3], and lymph nodes [LN] [normal, n = 8; AIH, n = 8]) from WT mice treated with normal liver‐derived exosome and AIH‐exosome treatments. P value significance represented by *, <0.05; **, <0.01; ***, <0.001; ****, <0.0001. F). RETN and MIF transcript levels were estimated after MBL2, FCN2, and CFP stimulation in BMMCs from HDs cultured with heat‐inactivated or normal plasma. G). Model of complement‐mediated platelet destruction in patients with ITP. Pathogens can trigger the complement activation of lectin pathways. Autoantibodies drive classical complement activation and mediate platelet destruction. In addition to classical complement activation, our findings revealed that the lectin pathway is a potential driver of platelet destruction mediated by exosomal FCN2, MBL2, and CFP. These pathways may further enhance the inflammatory responses. Complement activation is directly involved in platelet destruction and cross‐talk with amplified inflammatory responses including acquired immunity.