Bispecific Nanosystems Enable Multieffector Immune Cell Retargeting for Hematologic Malignancy Therapy

Abstract B‐cell lymphomas are hematologic malignancies characterized by poor prognoses. Immunotherapy has revolutionized B‐cell lymphoma treatment by harnessing immune effector cells, but current therapeutic strategies face limitations: suboptimal pharmacokinetics of bispecific antibodies and high complexity and cost of chimeric antigen receptor T‐cell therapies. To address these challenges, a bispecific nanosystem (biHSNPs) is developed that exploits the multi‐functional customizability of silica nanoplatform to conjugate antibodies targeting cytotoxic T cells or natural killer cells, alongside effector antibodies specific to B‐cells. Four biHSNPs with different effector and target antibodies are synthesized. This bispecific nanosystem enables simultaneous binding to immune effector cells and B‐cell lymphoma antigens, facilitating the formation of artificial immunological synapses. These synapses promote immune effector cell activation, leading to the release of cytotoxic proteins, while concurrently suppressing tumor cell proliferation and enhancing T‐cell activation. In vivo, biHSNPs effectively suppress tumor growth and activate T cells in a xenograft mouse model, showcasing their potential in precision therapy. Moreover, biHSNPs successfully overcome tumor immune evasion through dual‐target signal blockade. Using a straightforward and scalable strategy, a bispecific nanosystem is constructed that not only addresses the limitations of current bispecific antibody therapies but also represents a promising approach for the treatment of hematological malignancies.