Modular Vaccine Robots for Spatiotemporal Programming of the CD4 ⁺ T Cell–Myeloid Cell Axis

ABSTRACT Here, we developed a magnetically driven modular Janus vaccine robot (MVR) with orthogonally functional domains to achieve spatiotemporal coordination of CD4 ⁺ T cell‐myeloid cell‐mediated tumor killing. The oleic acid‐modified CoFe ₂ O ₄ (OA@CF) and carboxyl‐modified T cell‐targeting aptamers are selectively assembled onto the hydrophobic and hydrophilic domains of JSPs, respectively, which form an orthogonal surface structure capable of adhering on the cell membrane. The magnetic module enables the MVR to achieve membrane disruption, antigen release, capture, and magnetically guided delivery toward CD4 ⁺ T‐enriched invasive tumor margins. The aptamer module allows MVR to act as APC‐T cell engagers to enhance CD4 ⁺ T cell‐APC interactions and antigen presentation, triggering a feedforward loop that activates CD4 ⁺ T cells and promotes IFN‐γ‐dependent differentiation of myeloid cells into MHC‐II ⁺ APCs and iNOS ⁺ effector cells. Both in vitro and in vivo results demonstrate that MVRs elicit spatially organized, multi‐effector immune response and suppress both primary and distal tumors. This work presents a distinctive and modular vaccine strategy for spatiotemporal orchestration of the CD4 ⁺ T cell‐myeloid cell immune loop, improving local immune activation and establishing a self‐amplifying antitumor immune response.