Cell‐Free, Dendritic Cell‐Mimicking Extracellular Blebs for Molecularly Controlled Vaccination

AbstractDendritic cells (DCs) are prime targets for vaccination and immunotherapy. However, limited control over antigen presentation at a desired maturation status in these plastic materials remains a fundamental challenge in efficiently orchestrating a controlled immune response. DC‐derived extracellular vesicles (EVs) can overcome some of these issues, but have significant production challenges. Herein, this work employs a unique chemicallyinduced method for production of DC‐derived extracellular blebs (DC‐EBs) that overcome the barriers of DC and DC‐derived EV vaccines. DC‐EBs are molecular snapshots of DCs in time, cell‐like particles with fixed stimulatory profiles for controlled immune signaling. DC‐EBs are produced in an order of magnitude more quickly and efficiently than conventional EVs and display stable structural integrity and antigen presentation compared to live DCs. Multi‐omic analysis confirmed DC‐EBs are majorly pure plasma membrane vesicles that are homogeneous at the single‐vesicle level, critical for safe and effective vaccination. Immature versus mature molecular profiles on DC‐EBs exhibit molecularly modulated immune responses compared to live DCs, improving remission and survival of tumor‐challenged mice via generation of antigen‐specific T cells. For the first time, DC‐EBs make their case for use in vaccines and for their potential in modulating other immune responses, potentially in combination with other immunotherapeutics.