A Novel Engineering Cell Therapy Platform Mimicking the Immune Thrombocytopenia-Derived Platelets to Inhibit Cytokine Storm in Hemophagocytic Lymphohistiocytosis.

Hemophagocytic lymphohistiocytosis (HLH) is a common and highly fatal hyperinflammatory syndrome characterized by the aberrant activation of macrophages. To date, there is a lack of targeted therapies for HLH. It is validated that macrophages in HLH efficiently phagocytose anti-CD41-platelets (anti-CD41-PLTs) from immune thrombocytopenia (ITP) patients in previous research. Hence, the pathological mechanisms of ITP are mimicked and anti-CD41-PLTs are utilized to load the macrophage-toxic drug VP16 to construct macrophage-targetable engineered platelets anti-CD41-PLT-VP16, which is a novel targeted therapy against HLH. Both in vitro and in vivo studies demonstrate that anti-CD41-PLT-VP16 has excellent targeting and pro-macrophage apoptotic effects. In HLH model mice, anti-CD41-PLT-VP16 prevents hemophagocytosis and inhibits the cytokine storm. Mechanistic studies reveal that anti-CD41-PLT-VP16 increases the cytotoxicity of VP16, facilitating precise intervention in macrophages. Furthermore, it operates as a strategic "besieger" in diminishing hyperinflammation syndrome, which can indirectly prevent the abnormal activation of T cells and NK cells and reduce the Ab-dependent cell-mediated cytotoxicity effect. The first platelet-based clinical trial is ongoing. The results show that after treatment with anti-CD41-PLT-VP16, HLH patients have a threefold increase in the overall response rate compared to patients receiving conventional chemotherapy. In conclusion, anti-CD41-PLT-VP16 provides a general insight into hyperinflammation syndrome and offers a novel clinical therapeutic strategy for HLH.

Emerging platelet-based drug delivery systems.

Drug delivery systems are becoming increasingly utilized; however, a major challenge in this field is the insufficient target of tissues or cells. Although efforts with engineered nanoparticles have shown some success, issues with targeting, toxicity and immunogenicity persist. Conversely, living cells can be used as drug-delivery vehicles because they typically have innate targeting mechanisms and minimal adverse effects. As active participants in hemostasis, inflammation, and tumors, platelets have shown great potential in drug delivery. This review highlights platelet-based drug delivery systems, including platelet membrane engineering, platelet membrane coating, platelet cytoplasmic drug loading, genetic engineering, and synthetic/artificial platelets for different applications.

Identification of three immune molecular subtypes associated with immune profiles, immune checkpoints, and clinical outcome in multiple myeloma.

PURPOSE: To identify the immune molecular subtype for MM to help achieve individualized and precise targeted therapy. METHODS: The GDC API was used to download the TCGA-MM profile dataset, which contains 859 samples in total, all of which were anterior to the standard treatment after diagnosis. Moreover, 282, 298, and 258 samples were stage I, stage II, and stage III separately. We used the immune gene expression profile for consistent clustering; and used the R software package ConsensusClusterPlus to sort the immune molecular subtypes. Correlation between subtypes and clinical features, immunity, and prognosis was then analyzed. RESULTS: A total of 859 tumor samples were separated into these three subtypes, which were not meaningfully related to age or sex but showed a remarkable association with stage. The results suggested that obvious differences in immune metagene expression and expression of 10 immune checkpoint genes appeared among the three subtypes. CONCLUSION: The three subtypes are distinctly different in terms of immune metagenes, immune checkpoint molecules, and clinical prognosis. The discovery of the immune microenvironment of MM could further reveal the strategy for immunotherapy in MM and provide a promising candidate prognostic tool for survival.