As the prospect of engineering primary B-cells for cellular therapies in cancer, autoimmune diseases, and infectious diseases grows, there is an increasing demand for robust in vitro culture systems that effectively activate human B-cells isolated from peripheral blood for consistent and efficient expansion and differentiation into various effector phenotypes. Feeder cell-based systems have shown promise in providing long-term signaling for expanding B-cells in vitro. However, these co-culture systems necessitate more rigorous downstream processing to prevent various feeder cell-related contaminations in the final product, which limits their clinical potential. In this study, we introduce a microbead-based CD40L-presentation platform for stable and consistent activation of human naïve B-cells. By employing a completely synthetic in vitro culture approach integrating B-cell receptor, CD21 co-receptor, toll-like receptor (TLR-9), and cytokine signals, we demonstrate that naïve B-cells can differentiate into memory B-cells (IgD-CD38-/lo + CD27+) and antibody-secreting cells (IgD-CD38++CD27+). During this process, B-cells underwent up to a 50-fold expansion, accompanied by isotype class switching and low levels of somatic hypermutation, mimicking physiological events within the germinal center. The reproducible generation of highly expanded and differentiated effector B-cells from naïve B-cells of multiple donors positions this feeder-free in vitro synthetic niche as a promising platform for large-scale production of effector B-cell therapeutics.